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Obstetrician & Gynecologist (OB/GYN)
37 years of experience
Accepting new patients

Credentials

Education ?

Medical School Score
The University of Texas at San Antonio (1975)
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Awards & Distinctions ?

Awards  
Patients' Choice 5th Anniversary Award (2014)
Patients' Choice Award (2010 - 2014)
Compassionate Doctor Award - 5 Year Honoree (2014)
Compassionate Doctor Recognition (2010 - 2014)
Associations
American Board of Obstetrics and Gynecology

Affiliations ?

Dr. Henry is affiliated with 5 hospitals.

Hospital Affiliations

Score

Rankings

  • Texas Health Harris Methodist Hospital Fort Worth
    1301 Pennsylvania Ave, Fort Worth, TX 76104
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    Top 25%
  • Baylor All Saints Medical Centers
    1400 8th Ave, Fort Worth, TX 76104
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    Top 25%
  • TX Health Fort Worth
  • Harris Methodist Hospital
  • Baylor All Saints
  • Publications & Research

    Dr. Henry has contributed to 182 publications.
    Title Presidents' Statement on Who Recommendation on Hba1c for Diabetes Diagnosis.
    Date April 2012
    Journal Diabetes Research and Clinical Practice
    Title Speaking with One Voice on Worksite Wellness: the American Cancer Society, the American Diabetes Association, and the American Heart Association.
    Date January 2012
    Journal American Journal of Health Promotion : Ajhp
    Title Effect of Angiotensin Receptor Blockade on Insulin Sensitivity and Endothelial Function in Abdominally Obese Hypertensive Patients with Impaired Fasting Glucose.
    Date December 2011
    Journal Clinical Science (london, England : 1979)
    Excerpt

    AngII (angiotensin II) may contribute to cardiovascular risk in obesity via adverse effects on insulin sensitivity and endothelial function. In the present study, we examined the effects of ARB (angiotensin receptor blocker) therapy (losartan, 100 mg/day) on insulin sensitivity and endothelial function in 53 subjects with stage I hypertension, abdominal obesity and impaired fasting glucose. The study design was a randomized double-blinded parallel design placebo-controlled multi-centre trial of 8 weeks duration. We used the hyperinsulinaemic-euglycaemic clamp technique to measure insulin sensitivity (expressed as the 'M/I' value) and RH-PAT (reactive hyperaemia-peripheral arterial tonometry) to measure endothelial function. Additional measures included HOMA (homoeostasis model assessment)-B, an index of pancreatic β-cell function, and markers of inflammation [e.g. CRP (C-reactive protein)] and oxidative stress (e.g. F2-isoprostanes). ARB therapy did not alter insulin sensitivity [5.2 (2.7) pre-treatment and 4.6 (1.6) post-treatment] compared with placebo therapy [6.1 (2.9) pre-treatment and 5.3 (2.7) post-treatment; P value not significant], but did improve the HOMA-B compared with placebo therapy (P=0.05). ARB therapy also did not change endothelial function [RH-PAT, 2.15 (0.7) pre-treatment and 2.11 (0.7) post-treatment] compared with placebo therapy [RH-PAT, 1.81 (0.5) pre-treatment and 1.76 (0.7) post-treatment; P value not significant]. Markers of inflammation and oxidative stress were not significantly changed by ARB therapy. In conclusion, ARB therapy did not alter peripheral insulin sensitivity or endothelial function in this cohort of patients with essential hypertension, abdominal obesity and impaired fasting glucose, but did improve pancreatic β-cell function.

    Title Folate Pathway and Nonsyndromic Cleft Lip and Palate.
    Date May 2011
    Journal Birth Defects Research. Part A, Clinical and Molecular Teratology
    Excerpt

    Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common complex birth defect. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs), C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. Here, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP, and were there detectable interactions between these genes and environmental exposures?

    Title Increased Srf Transcriptional Activity in Human and Mouse Skeletal Muscle is a Signature of Insulin Resistance.
    Date April 2011
    Journal The Journal of Clinical Investigation
    Excerpt

    Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) for which the molecular mediators remain unclear. We therefore conducted an expression analysis of human muscle biopsies from patients with T2D; normoglycemic but insulin-resistant subjects with a parental family history (FH(+)) of T2D; and family history-negative control individuals (FH(–)). Actin cytoskeleton genes regulated by serum response factor (SRF) and its coactivator megakaryoblastic leukemia 1 (MKL1) had increased expression in T2D and FH(+) groups. Furthermore, striated muscle activator of Rho signaling (STARS), an activator of SRF, was upregulated in T2D and FH(+) and was inversely correlated with insulin sensitivity. Skeletal muscle from insulin-resistant mice recapitulated this gene expression pattern and showed reduced G-actin and increased nuclear localization of MKL1, each of which regulates SRF activity. Overexpression of MKL1 or reduction in G-actin decreased insulin-stimulated Akt phosphorylation, whereas reduction of STARS expression increased insulin signaling and glucose uptake. Pharmacological SRF inhibition by CCG-1423 reduced nuclear MKL1 and improved glucose uptake and tolerance in insulin-resistant mice in vivo. Thus, SRF pathway alterations are linked to insulin resistance, may contribute to T2D pathogenesis, and could represent therapeutic targets.

    Title Effects of Intensive Insulin Therapy Alone and with Added Pioglitazone on Renal Salt/water Balance and Fluid Compartment Shifts in Type 2 Diabetes.
    Date January 2011
    Journal Diabetes, Obesity & Metabolism
    Excerpt

    To evaluate the effects of intensive insulin therapy alone or with added pioglitazone on renal salt/water balance and body fluid compartment shifts in type 2 diabetes.

    Title Determinants of Glucose Tolerance in Impaired Glucose Tolerance at Baseline in the Actos Now for Prevention of Diabetes (act Now) Study.
    Date October 2010
    Journal Diabetologia
    Excerpt

    The aim of the study was to examine the determinants of oral glucose tolerance in 602 persons with impaired glucose tolerance (IGT) who participated in the Actos Now for Prevention of Diabetes (ACT NOW) study.

    Title Sglt2 Inhibition--a Novel Strategy for Diabetes Treatment.
    Date July 2010
    Journal Nature Reviews. Drug Discovery
    Excerpt

    Inhibiting sodium-glucose co-transporters (SGLTs), which have a key role in the reabsorption of glucose in the kidney, has been proposed as a novel therapeutic strategy for diabetes. Genetic mutations in the kidney-specific SGLT2 isoform that result in benign renal glycosuria, as well as preclinical and clinical studies with SGLT2 inhibitors in type 2 diabetes, support the potential of this approach. These investigations indicate that elevating renal glucose excretion by suppressing SGLT2 can reduce plasma glucose levels, as well as decrease weight. Although data from ongoing Phase III trials of these agents are needed to more fully assess safety, results suggest that the beneficial effects of SGLT2 inhibition might be achieved without exerting significant side effects--an advantage over many current diabetes medications. This article discusses the role of SGLT2 in glucose homeostasis and the evidence available so far on the therapeutic potential of blocking these transporters in the treatment of diabetes.

    Title Gsk-3beta and Control of Glucose Metabolism and Insulin Action in Human Skeletal Muscle.
    Date July 2010
    Journal Molecular and Cellular Endocrinology
    Excerpt

    The involvement of the beta-isoform of glycogen synthase kinase (GSK-3) in glucose metabolism and insulin action was investigated in cultured human skeletal muscle cells. A 60% reduction in GSK-3beta protein expression was attained by treatment with siRNA; GSK-3alpha expression was unaltered. GSK-3beta knockdown did not influence total glycogen synthase (GS) activity, but increased the phosphorylation-dependent activity (fractional velocity-FV) in the basal state. Insulin responsiveness of GSFV was doubled by GSK-3beta knockdown (p<0.05). Basal rates of glucose uptake (GU) were not significantly influenced by GSK-3beta knockdown, while insulin stimulation of GU was increased. Improvements in insulin action on GS and GU did not involve changes in protein expression of either IRS-1 or Akt 1/2. Maximal insulin stimulation of phosphorylation of Akt was unaltered by GSK-3beta knockdown. Unlike GSK-3alpha, GSK-3beta directly regulates both GS activity in the absence of added insulin and through control of insulin action.

    Title Managing Type 2 Diabetes: Balancing Hba1c and Body Weight.
    Date June 2010
    Journal Postgraduate Medicine
    Excerpt

    Most patients with type 2 diabetes present with comorbid overweight or obesity. Reaching and maintaining acceptable glycemic control is more difficult in overweight and obese patients, and these conditions are associated with increased risk for cardiovascular and other diseases. Glycemic management for these patients is complicated by the fact that insulin and many of the oral medications available to treat type 2 diabetes produce additional weight gain. However, an increasing number of therapeutic options are available that are weight neutral or lead to weight loss in addition to their glycemic benefits. This article evaluates the evidence from clinical trials regarding the relative glycemic benefits, measured in terms of glycated hemoglobin change, versus the impact on body weight of each medication currently approved for type 2 diabetes. In general, the sulfonylureas, thiazolidinediones, and D-phenylalanine derivatives have been shown to promote weight gain. The dipeptidyl peptidase-4 inhibitors are weight neutral, while the biguanides, incretin mimetics, and amylin mimetics promote weight loss. Trials examining the glycemic benefits of the weight loss agents orlistat and sibutramine are also examined. Awareness of this evidence base can be used to inform medication selection in support of weight management goals for patients with type 2 diabetes.

    Title Effects of Incretin Hormones on Beta-cell Mass and Function, Body Weight, and Hepatic and Myocardial Function.
    Date March 2010
    Journal The American Journal of Medicine
    Excerpt

    Type 2 diabetes mellitus is a chronic debilitating disease characterized by insulin resistance and progressive pancreatic dysfunction. Concomitant with declining pancreatic function and decreasing insulin production, there is a progressive increase in blood glucose levels. Hyperglycemia plays a major role in the development of the microvascular and macrovascular complications of diabetes. Traditional agents used for the treatment of type 2 diabetes are able to improve glycemia, but their use is often limited by treatment-associated side effects, including hypoglycemia, weight gain, and edema. Moreover, these agents do not have any sustained effect on beta-cell mass or function. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both exenatide (the first dipeptidyl peptidase-4-resistant glucagonlike peptide-1 receptor agonist approved by the US Food and Drug Administration [FDA]), and liraglutide (a long-acting incretin mimetic), improve beta-cell function and glycemia with minimal hypoglycemia. Both agents have trophic effects on beta-cell mass in animal studies. The use of these agents is also associated with reduced body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic function, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes.

    Title Actos Now for the Prevention of Diabetes (act Now) Study.
    Date December 2009
    Journal Bmc Endocrine Disorders
    Excerpt

    Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial.

    Title Pharmacotherapy of Hyperglycemia.
    Date November 2009
    Journal Expert Opinion on Pharmacotherapy
    Excerpt

    Type 2 diabetes mellitus (T2DM) is a chronic, progressive disorder that affects more than 230 million people worldwide and is expected to affect 366 million by 2030. Both the prevalence of T2DM and the cost of its long term complications has driven the focus and emphasis on treatments aimed at reducing hyperglycemia and controlling hypertension and dyslipidemia. In the last 5 years new glucose lowering drugs acting on novel pathways have been developed, licensed and launched. These drugs include the glucagon-like peptide (GLP-1) agonists, exenatide, and dipeptidyl peptidase (DPP-IV) inhibitors such as sitagliptin and saxagliptin. This review describes current approaches to T2DM treatment, focusing on newer agents which tend to be associated with less hypoglycemia and possible weight loss, and addresses the potential roles of novel oral pharmacologic agents in the late-stages of development that might provide new options for the management of this disease.

    Title Selective Regulation of Cellular and Secreted Multimeric Adiponectin by Antidiabetic Therapies in Humans.
    Date September 2009
    Journal American Journal of Physiology. Endocrinology and Metabolism
    Excerpt

    Adiponectin, an insulin-sensitizing factor secreted from adipose tissue, is decreased in individuals with type 2 diabetes (T2D) and increased in response to thiazolidinedione (TZD) therapy. Changes in its secretion and assembly into higher-order forms affect insulin sensitivity. To determine the relative potency of TZDs on intra-adipocyte multimerization and secretion of adiponectin, we assessed the impact of in vivo low- or high-dose rosiglitazone treatment alone or combined with metformin in subjects with T2D. T2D subjects received high-dose rosiglitazone (8 mg/day), high-dose metformin (2,000 mg/day), or low-dose combination rosiglitazone-metformin therapy (4 mg + 1,000 mg/day) for 4 mo. All subjects were then switched to high-dose rosiglitazone-metformin combination therapy (8 mg + 2,000 mg/day) for another 4 mo. Low-dose rosiglitazone increased serum adiponectin, whereas the high dose increased both adipocyte content and serum adiponectin levels. TZDs selectively increased the percentage of circulating adiponectin in the potent, high-molecular-weight (HMW) form. No TZD effects were evident on multimer distribution in the cell. Expression of the chaperone protein ERp44, which retains adiponectin within the cell, was decreased by TZD treatment. No changes occurred in Ero1-Lalpha expression. Metformin had no effect on any of these measures. Increases in adiponectin correlated with improvements in insulin sensitivity. In vivo, TZDs have apparent dose-dependent effects on cellular and secreted adiponectin. TZD-mediated improvements in whole body insulin sensitivity are associated with increases in circulating but not cellular levels of the HMW adiponectin multimer. Finally, TZDs promote the selective secretion of HMW adiponectin, potentially, in part, through decreasing the expression of the adiponectin-retaining protein ERp44.

    Title Incretin Therapies: Effects Beyond Glycemic Control.
    Date August 2009
    Journal European Journal of Internal Medicine
    Excerpt

    Impaired insulin secretion plays a major role in the pathogenesis of type 2 diabetes mellitus, and progressive loss of beta-cell function is a pathophysiologic hallmark of type 2 diabetes. Recent science has elaborated on the role of the incretin hormones on beta-cell function and insulin secretion, as well as the role that incretin-based pharmacotherapies may have on glycemic control and beta-cell function, possibly altering the progressive loss of beta-cell function and possibly reversing/halting disease progression. However, incretin-based therapies may also have benefits extending beyond glycemic control and insulin secretion. In this review we examine some of those "beyond-glycemic" benefits, including presentation of data on weight reduction, blood pressure lowering, beneficial changes in the lipid profile, and improvements in myocardial and endothelial function. We investigate how those effects may help ameliorate the cardiovascular burden in patients with diabetes.

    Title Effect of the Dual Peroxisome Proliferator-activated Receptor-alpha/gamma Agonist Aleglitazar on Risk of Cardiovascular Disease in Patients with Type 2 Diabetes (synchrony): a Phase Ii, Randomised, Dose-ranging Study.
    Date July 2009
    Journal Lancet
    Excerpt

    Despite previous reports of potential adverse cardiovascular effects of peroxisome proliferator-activated receptor (PPAR) agonists, the promise for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes is of continued interest. The SYNCHRONY study aimed to establish the glucose-lowering and lipid-modifying effects, and safety profile, of the dual PPAR-alpha and PPAR-gamma agonist aleglitazar.

    Title Incretin Therapies: Effects Beyond Glycemic Control.
    Date June 2009
    Journal The American Journal of Medicine
    Excerpt

    Impaired insulin secretion plays a major role in the pathogenesis of type 2 diabetes mellitus, and progressive loss of beta-cell function is a pathophysiologic hallmark of type 2 diabetes. Recent science has elaborated on the role of the incretin hormones on beta-cell function and insulin secretion, as well as the role that incretin-based pharmacotherapies may have on glycemic control and beta-cell function, possibly altering the progressive loss of beta-cell function and possibly reversing/halting disease progression. However, incretin-based therapies may also have benefits extending beyond glycemic control and insulin secretion. In this review we examine some of those "beyond-glycemic" benefits, including presentation of data on weight reduction, blood pressure lowering, beneficial changes in the lipid profile, and improvements in myocardial and endothelial function. We investigate how those effects may help ameliorate the cardiovascular burden in patients with diabetes.

    Title Response of Adiponectin and Its Receptors to Changes in Metabolic State After Gastric Bypass Surgery: Dissociation Between Adipose Tissue Expression and Circulating Levels.
    Date June 2009
    Journal Surgery for Obesity and Related Diseases : Official Journal of the American Society for Bariatric Surgery
    Excerpt

    Adiponectin is an adipokine with anti-atherogenic and insulin-sensitizing properties. Specific adiponectin receptors, adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2), are present in adipose tissue, indicating adiponectin might have autocrine/paracrine effects on its production or action. In addition, endoplasmic reticulum oxidoreductase 1-Lalpha might mediate regulation of its secretion. The study aim was to determine the subcutaneous adipose tissue (SAT) adiponectin gene and protein expression and their correlation to metabolic parameters during metabolically distinct times after gastric bypass surgery.

    Title The Role of Incretins in Cardiovascular Control.
    Date April 2009
    Journal Current Hypertension Reports
    Excerpt

    Glucagon-like peptide-1 (GLP-1) is an incretin secreted in response to nutrient ingestion. Understanding the incretin effect on diabetes pathophysiology has led to development of a new class of agents termed incretin mimetics. Exenatide is the first GLP-1 agonist approved to treat type 2 diabetes mellitus (T2DM). Clinical studies have demonstrated exenatide's efficacy in improving glycemic control, often coupled with weight loss. Studies are investigating the potential cardiovascular benefits of GLP-1 agonists. Blood pressure, cholesterol levels, C-reactive protein, and insulin resistance may improve in patients treated with exenatide. The direct effect of GLP-1 on cardiac myocytes and vascular smooth muscle has been an active area of investigation. Infusions of GLP-1 in animal models and human subjects with heart failure have demonstrated significantly improved cardia parameters. In patients with T2DM, GLP-1 infusion has been shown to improve endothelial function, irrespective of changes in insulin sensitivity. These pilot studies provide a foundation for developing therapies aimed at modulating incretin physiology for the additional benefit on the cardiovascular system in patients with T2DM and heart disease.

    Title Myotoxic Reactions to Lipid-lowering Therapy Are Associated with Altered Oxidation of Fatty Acids.
    Date April 2009
    Journal Endocrine
    Excerpt

    Despite exceptional efficacy and safety, fear of muscle toxicity remains a major reason statins are underutilized. Evidence suggests that statin muscle toxicity may be mediated by abnormalities in lipid metabolism. To test the hypothesis that myotubes from patients intolerant of lipid-lowering therapies have abnormal fatty acid oxidation (FAO) responses we compared muscle from 11 subjects with statin intolerance (Intolerant) with muscle from seven statin-naive volunteers undergoing knee arthroplasty (Comparator). Gross muscle pathology was graded and skeletal muscle cell cultures were produced from each subject. FAO was assessed following treatment with increasing statin concentrations. There was no difference in muscle biopsy myopathy scores between the groups. Basal octanoate oxidation was greater in Intolerant than in Comparator subjects (P = 0.03). Lovastatin-stimulated palmitate oxidation tended to be greater for Intolerant compared to Control subjects' myotubes (P = 0.07 for 5 microM and P = 0.06 for 20 microM lovastatin). In conclusion abnormalities in FAO of Intolerant subjects appear to be an intrinsic characteristic of these subjects that can be measured in their cultured myotubes.

    Title Metabolic and Hormonal Changes Induced by Pioglitazone in Polycystic Ovary Syndrome: a Randomized, Placebo-controlled Clinical Trial.
    Date March 2009
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    Polycystic ovary syndrome (PCOS) is characterized by insulin resistance, compensatory hyperinsulinemia, increased prevalence of impaired glucose tolerance, and increased ovarian androgen biosynthesis.

    Title Polycystic Ovary Syndrome is Associated with Tissue-specific Differences in Insulin Resistance.
    Date February 2009
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    The potential differential contributions of skeletal muscle and adipose tissue to whole body insulin resistance were evaluated in subjects with polycystic ovary syndrome (PCOS). Research Design and

    Title Evolving Concepts of Type 2 Diabetes Management with Oral Medications: New Approaches to an Old Disease.
    Date December 2008
    Journal Current Medical Research and Opinion
    Excerpt

    Type 2 diabetes is often accompanied by co-morbid conditions such as hypertension and dyslipidemia, which, coupled with persistent hyperglycemia, result in significant macrovascular and microvascular complications. Type 2 diabetes treatments focus primarily on controlling hyperglycemia, hypertension, and dyslipidemia to stabilize the disease and minimize complications. Despite treatment, control of hyperglycemia and the conditions associated with type 2 diabetes are suboptimal in the majority of patients. Research efforts have concentrated on the development of new therapies for type 2 diabetes, including agents that could be used both as monotherapy and in combination with established oral antidiabetic agents to improve glycemic control and reduce the disease burden on patients.

    Title Adiponectin Secretion and Response to Pioglitazone is Depot Dependent in Cultured Human Adipose Tissue.
    Date November 2008
    Journal American Journal of Physiology. Endocrinology and Metabolism
    Excerpt

    The subcutaneous (S) and visceral (V) adipose tissue (AT) depots are increasingly recognized as distinct. To test the hypothesis that depot differences exist for adiponectin, fresh and cultured human VAT and SAT from obese type 2 diabetic (T2D) and obese nondiabetic (ND) subjects was examined to determine whether differences in adiponectin content and secretion occurred as a function of depot studied, diabetic status, and response to thiazolidinedione treatment. VAT and SAT were obtained by biopsy and AT explants cultured in defined media for 7 days. Protein expression was assessed by Western blot. Adiponectin content of conditioned medium was determined by radioimmunoassay. Diabetic status had no effect on adiponectin secretion over days 0-2 of culture. In ND SAT, secretion fell over days 2-4 but was sustained at greater levels vs. T2D SAT. In both ND and T2D VAT, adiponectin secretion was low, similar to T2D SAT. Over the 7-day culture period, cellular adiponectin increased in ND SAT and VAT; it remained unchanged in T2D SAT and VAT. Pioglitazone increased adiponectin secretion and content in all SAT. Pioglitazone failed to increase adiponectin secretion from either ND or T2D VAT and increased cellular content only in ND VAT. AT depot differences exist in the secretion of adiponectin and responsiveness to thiazolidinedione treatment. These data suggest that SAT, not VAT, appears to be the major contributor to increased circulating adiponectin levels in response to pioglitazone treatment.

    Title Development of an Enzyme-linked Immunosorbent Assay for the Detection of Humoral Antibody to Pasteurella Anatipestifer.
    Date September 2008
    Journal Avian Pathology : Journal of the W.v.p.a
    Excerpt

    An enzyme-linked immunosorbent assay (ELISA) for the detection of antibodies to Pasteurella anatipestifer in duck sera is described. As part of the initial assay development, micro-titration plates from different manufacturers were assayed for their suitability to bind P. anatipestifer antigen. The Nunc Immunopiate II was chosen, on account of its overall reproducibility (5.5% coefficient of variation) and the absence of an edge effect. Optimum concentrations of reagents were determined and the inclusion of 1.0M NaCl in the wash buffer was found to reduce non-specific binding and increase assay sensitivity. The assay is specific in that antibodies were detected only in those ducks either exposed to or following vaccination with P. anatipestifer; sera from ducks immunised with other heterologous bacterial antigens, and having agglutinating antibodies to them, gave no detectable response in the ELISA. Between-assay coefficients of variation for the quality control serum pools representing high, medium and low levels of antibodies to P. anatipestifer were 6.8%, 8.3% and 8.6% respectively. A precision-dose profile was derived. A graph of absorbance versus log(2) serum end point titre showed a linear relationship (r = 0.99) over the range investigated. The derived regression line (P<0.001) was used to transform the absorbance measurement obtained for a single 1:100 dilution of serum into a log(2) titre value. It was demonstrated that the ELISA is a much superior method to rapid slide agglutination and agar gel precipitin tests in measuring antibody responses to exposure against P. anatipestifer type 2.

    Title Circulating and Cellular Adiponectin in Polycystic Ovary Syndrome: Relationship to Glucose Tolerance and Insulin Action.
    Date June 2008
    Journal Fertility and Sterility
    Excerpt

    OBJECTIVE: To evaluate serum adiponectin levels and organization into multimers in women with polycystic ovary syndrome (PCOS) and assess relationships between adiponectin, glucose tolerance, and insulin resistance. DESIGN: In vivo and in vitro study. SETTING: Outpatient clinic at university and Veterans hospitals in the United States and university laboratory. PATIENT(S): Thirty-one obese women with PCOS and six age- and body mass index (BMI)-matched normal cycling control subjects. INTERVENTION(S): All subjects studied in the fasting state. MAIN OUTCOME MEASURE(S): A 75-g oral glucose tolerance test (OGTT), hyperinsulinemic/euglycemic clamp, circulating adiponectin levels, adipocyte adiponectin content, and organization of adiponectin into multimeric forms. RESULT(S): Whole body insulin action (glucose disposal rate, 5.61 +/- 2.90 vs. 8.79 +/- 0.81 mg/kg/min, PCOS and control) and adiponectin levels (9.5 +/- 0.7 7 vs. 17.4 +/- 1 microg/mL, PCOS vs. control) were significantly reduced in the subjects with PCOS. There were significant correlations between glucose tolerance, insulin action, and circulating adiponectin levels in all subjects. The content of adiponectin protein was reduced in subcutaneous adipocytes from subjects with PCOS (252 +/- 31 vs. 388 +/- 58 arbitrary units/10 microg protein). Subjects with PCOS had less of their circulating adiponectin organized into high molecular weight (HMW) multimeric complexes. Glucose-intolerant subjects with PCOS also had less intracellular HMW adiponectin. CONCLUSION(S): Both circulating adiponectin levels and the portion present as the most active HMW form are reduced in PCOS, with differences related to the degree of glucose intolerance and insulin resistance.

    Title Exenatide As a Treatment for Diabetes and Obesity: Implications for Cardiovascular Risk Reduction.
    Date May 2008
    Journal Current Atherosclerosis Reports
    Excerpt

    Among the challenges in improving outcomes in patients with diabetes is effectively implementing existing pharmacotherapies. However, current therapies for diabetes are often limited by adverse effects such as edema, hypoglycemia, and weight gain. Understanding the role of the incretin effect on the pathophysiology of diabetes has led to the development of new therapeutic agents. Exenatide is the first in a new class of agents termed "incretin mimetics," which replicate several glucoregulatory effects of the endogenous incretin hormone, glucagon-like peptide-1. In clinical trials, patients with type 2 diabetes treated with exenatide demonstrate sustained improvements in glycemic control, with reductions in fasting and postprandial glucose levels and improvements in glycosylated hemoglobin levels. Improvements in glycemic control with exenatide are coupled with reductions in body weight. Lipid parameters, blood pressure, and C-reactive protein have been shown to improve favorably in patients treated with exenatide. The sustained glycemic improvements and progressive reduction in body weight with exenatide treatment support a shift toward a more favorable cardiovascular risk profile and may have a positive impact on decreasing the risk of associated long-term complications.

    Title Pathogenic Potential of Adipose Tissue and Metabolic Consequences of Adipocyte Hypertrophy and Increased Visceral Adiposity.
    Date April 2008
    Journal Expert Review of Cardiovascular Therapy
    Excerpt

    When caloric intake exceeds caloric expenditure, the positive caloric balance and storage of energy in adipose tissue often causes adipocyte hypertrophy and visceral adipose tissue accumulation. These pathogenic anatomic abnormalities may incite metabolic and immune responses that promote Type 2 diabetes mellitus, hypertension and dyslipidemia. These are the most common metabolic diseases managed by clinicians and are all major cardiovascular disease risk factors. 'Disease' is traditionally characterized as anatomic and physiologic abnormalities of an organ or organ system that contributes to adverse health consequences. Using this definition, pathogenic adipose tissue is no less a disease than diseases of other body organs. This review describes the consequences of pathogenic fat cell hypertrophy and visceral adiposity, emphasizing the mechanistic contributions of genetic and environmental predispositions, adipogenesis, fat storage, free fatty acid metabolism, adipocyte factors and inflammation. Appreciating the full pathogenic potential of adipose tissue requires an integrated perspective, recognizing the importance of 'cross-talk' and interactions between adipose tissue and other body systems. Thus, the adverse metabolic consequences that accompany fat cell hypertrophy and visceral adiposity are best viewed as a pathologic partnership between the pathogenic potential adipose tissue and the inherited or acquired limitations and/or impairments of other body organs. A better understanding of the physiological and pathological interplay of pathogenic adipose tissue with other organs and organ systems may assist in developing better strategies in treating metabolic disease and reducing cardiovascular disease risk.

    Title Role of Glycogen Synthase Kinase-3 Alpha in Insulin Action in Cultured Human Skeletal Muscle Cells.
    Date September 2007
    Journal Endocrinology
    Excerpt

    An association between glycogen synthase kinase-3 (GSK3) in skeletal muscle and insulin resistance has been demonstrated in type 2 diabetic patients. In addition, inhibition of GSK3 improves insulin action. The aim of the present study was to elucidate the role of the alpha-isoform of GSK3 in insulin resistance in human skeletal muscle cells from nondiabetic subjects maintained in culture. Transfection of muscle cells with specific antisense oligonucleotides resulted in a 30-50% decrease of GSK3alpha protein expression (P < 0.05). Whereas neither the basal fractional velocity of glycogen synthase (GS FV) (an indicator of the activation state of the enzyme) nor glucose uptake (GU) were altered, reducing GSK3alpha expression resulted in increases in insulin stimulation of both GS FV and GU. GSK3alpha overexpression (60-100% increase over control) did not alter basal GS FV or GU but impaired insulin stimulation of both responses. Knockdown of GSK alpha also led to an increase in insulin receptor substrate-1 protein expression but did not alter insulin stimulation of pS473-Akt phosphorylation. However, GSK3alpha overexpression impaired insulin action on pS473-Akt. In summary, we concluded the following: 1) modulation of GSK3alpha expression has no effect on basal GU and glycogen synthase activities; 2) reduction of GSK3alpha expression results in improvements in insulin action; and 3) elevation of GSK3alpha in human skeletal muscle cells can induce insulin resistance for several responses. We conclude that GSK3alpha is an important regulator of muscle insulin action.

    Title Inhaled Insulin in Patients with Asthma and Chronic Obstructive Pulmonary Disease.
    Date September 2007
    Journal Diabetes Technology & Therapeutics
    Excerpt

    The effect of inhaled insulin in subjects with diabetes and chronic lung disease, such as asthma or chronic obstructive pulmonary disease (COPD), is of particular interest because these diseases are quite common, and it is likely that patients with asthma or COPD who are poorly controlled on oral agents and are reluctant to start subcutaneous insulin would benefit from inhaled insulin to improve their glucose control. Since patients with asthma or COPD have varied pulmonary symptoms and abnormal pulmonary function, it is important to establish the pulmonary safety and efficacy of inhaled insulin in subjects with diabetes and asthma or COPD. Pharmacokinetic and pharmacodynamic studies in non-diabetic subjects with asthma consistently show lower absorption of inhaled insulin and lesser glucose lowering effects by approximately 30-40%, as compared to subjects without asthma. Thus, it would be expected that the dose of insulin required to obtain equivalent glycemic control would be higher by approximately 30-40% in subjects with asthma and diabetes (as compared to subjects without asthma but with diabetes). However, prior administration of a bronchodilator inhaler in individuals with asthma and diabetes reverses airway obstruction and thus may obviate the need for increased insulin requirements. In contrast to patients with asthma, in patients with COPD and diabetes, the absorption of inhaled insulin appears to be variable (higher or lower than in non-COPD subjects). Whether this variability is secondary to differences in inhalation devices or different study populations is not clear at present. Overall, data from the clinical studies indicate that inhaled insulin is effective and well tolerated in subjects with diabetes and chronic lung disease. However, preliminary, limited data from the longer-term clinical studies suggest that there is a marginally greater decline in pulmonary function tests in subjects with asthma/COPD and diabetes compared to subjects with diabetes and no chronic lung disease. Thus, there is a clear need for longer-term studies in subjects with diabetes and chronic lung disease in order to further clarify the safety and efficacy of inhaled insulin in this population.

    Title Electron Paramagnetic Spectroscopic Evidence of Exercise-induced Free Radical Accumulation in Human Skeletal Muscle.
    Date June 2007
    Journal Free Radical Research
    Excerpt

    The present study determined if acute exercise increased free radical formation in human skeletal muscle. Vastus lateralis biopsies were obtained in a randomized balanced order from six males at rest and following single-leg knee extensor exercise performed for 2 min at 50% of maximal work rate (WR(MAX)) and 3 min at 100% WR(MAX). EPR spectroscopy revealed an exercise-induced increase in mitochondrial ubisemiquinone (UQ*-) [0.167 +/- 0.055 vs. rest: 0.106 +/- 0.047 arbitrary units (AU)/g total protein (TP), P < 0.05] and alpha-phenyl-tert-butylnitrone-adducts (112 +/- 41 vs. rest: 29 +/- 9 AU/mg tissue mass, P < 0.05). Intramuscular lipid hydroperoxides also increased (0.320 +/- 0.263 vs. rest: 0.148 +/- 0.071 nmol/mg TP, P < 0.05) despite an uptake of alpha-tocopherol, alpha-carotene and beta-carotene. There were no relationships between mitochondrial volume density and any biomarkers of oxidative stress. These findings provide the first direct evidence for intramuscular free radical accumulation and lipid peroxidation following acute exercise in humans.

    Title Adiponectin in Health and Disease.
    Date June 2007
    Journal Diabetes, Obesity & Metabolism
    Excerpt

    Adipose tissue is an active metabolic tissue that secretes multiple metabolically important proteins, known as adipokines. Adiponectin is an important adipokine because of its beneficial effects on glucose and lipid metabolism. Low levels of adiponectin are associated with disease states such as diabetes and cardiovascular disease. Direct administration of adiponectin has been shown to be beneficial in animal models of diabetes, obesity and atherosclerosis. Adiponectin levels in humans can be increased through indirect methods such as weight loss or treatment with thiazolidinediones. This article will review the epidemiology and therapeutic options with adiponectin.

    Title Impaired Fasting Glucose and Impaired Glucose Tolerance: Implications for Care.
    Date April 2007
    Journal Diabetes Care
    Title Cardiometabolic Risk Modification: Current Trends and Emerging Therapies.
    Date March 2007
    Journal Jaapa : Official Journal of the American Academy of Physician Assistants
    Title Exenatide Elicits Sustained Glycaemic Control and Progressive Reduction of Body Weight in Patients with Type 2 Diabetes Inadequately Controlled by Sulphonylureas with or Without Metformin.
    Date December 2006
    Journal Diabetes/metabolism Research and Reviews
    Excerpt

    BACKGROUND: In two placebo-controlled 30-week trials, treatment with exenatide reduced HbA(1c) and body weight in patients with type 2 diabetes in the context of sulphonylurea (SU) or SU plus metformin (MET) as background treatment. This analysis examines the effects of 82 weeks of exenatide treatment for participants in these earlier 30-week trials. METHODS: Data were pooled from the two pivotal trials of exenatide added to SU or SU plus MET. Both 30-week, placebo-controlled trials of 5 microg or 10 microg exenatide b.i.d. were followed by 52-week open-label, uncontrolled extension studies in which all participants received 10 microg exenatide b.i.d. and continued prior oral therapies. This interim analysis includes data for 222 patients who completed 82 weeks of exenatide treatment (61% M, age 57 +/- 10 y, weight 99 +/- 21 kg, BMI 34 +/- 6 kg/m(2), HbA(1c)8.4 +/- 1.0% [mean +/- SD]). RESULTS: Reduction in HbA(1c) from baseline to week 30 (-0.8 +/- 0.1% and -1.0 +/- 0.1% for 5 microg b.i.d. and 10 microg b.i.d., respectively [mean +/- SE]) was sustained up to week 82 (-1.0 +/- 0.1%). Of 207 patients with baseline HbA(1c) > 7%, 44% achieved HbA(1c) < or = 7% at week 82. Reduction of body weight from baseline to week 30 (-1.4 +/- 0.3 kg and -2.1 +/- 0.3 kg for 5 microg b.i.d. and 10 microg b.i.d., respectively) was progressive up to week 82 (-4.0 +/- 0.3 kg). The most frequent adverse events were nausea and hypoglycaemia, both generally mild to moderate in intensity. CONCLUSIONS: Exenatide added to maximally effective doses of SU or SU plus MET resulted in a sustained reduction in HbA(1c) and a progressive reduction in weight over 1 1/2 years.

    Title Tissue-specific Expression and Regulation of Gsk-3 in Human Skeletal Muscle and Adipose Tissue.
    Date November 2006
    Journal American Journal of Physiology. Endocrinology and Metabolism
    Excerpt

    Glycogen synthase kinase-3 (GSK-3) is a ubiquitous kinase implicated in both insulin action and adipogenesis. To determine how these multiple roles may relate to insulin resistance, we studied the regulation of GSK-3 protein expression and phosphorylation in skeletal muscle and isolated adipocytes from nonobese healthy control (HC), obese control (OC), and obese type 2 diabetic (OT2D) subjects. At baseline there were no differences in the GSK-3 protein expression in adipocytes. OC subjects underwent a 6-mo caloric restriction resulting in a 7% decrease in body mass index (BMI) and a 21% improvement in insulin-stimulated whole body glucose disposal rate (GDR). GSK-3alpha and GSK-3beta expression decreased in adipocytes (P < 0.05), whereas GSK-3alpha protein expression increased in skeletal muscle (P < 0.05). OT2D subjects were treated with troglitazone or metformin for 3-4 mo. After troglitazone treatment GDR improved (P < 0.05) despite an increase in BMI (P < 0.05), whereas metformin had no significant effect on GDR. There was no significant change in GSK-3 expression in adipocytes following troglitazone, whereas both GSK-3alpha and -beta were decreased in skeletal muscle (P < 0.05). Metformin treatment had no significant impact on GSK-3 protein expression in either adipocytes or skeletal muscle. Neither treatment influenced GSK-3 serine phosphorylation in skeletal muscle or adipocytes. These results suggest that there is tissue specificity for the regulation of GSK-3 in humans. In skeletal muscle GSK-3 plays a role in control of metabolism and insulin action, whereas the function in adipose tissue is less clear.

    Title Retinol-binding Protein 4 and Insulin Resistance in Lean, Obese, and Diabetic Subjects.
    Date June 2006
    Journal The New England Journal of Medicine
    Excerpt

    Insulin resistance has a causal role in type 2 diabetes. Serum levels of retinol-binding protein 4 (RBP4), a protein secreted by adipocytes, are increased in insulin-resistant states. Experiments in mice suggest that elevated RBP4 levels cause insulin resistance. We sought to determine whether serum RBP4 levels correlate with insulin resistance and change after an intervention that improves insulin sensitivity. We also determined whether elevated serum RBP4 levels are associated with reduced expression of glucose transporter 4 (GLUT4) in adipocytes, an early pathological feature of insulin resistance.

    Title Diabetes Treatments Have Differential Effects on Nontraditional Cardiovascular Risk Factors.
    Date May 2006
    Journal Journal of Diabetes and Its Complications
    Excerpt

    OBJECTIVE: The aim of this study was to determine the effect of basal insulin, alone or with a sensitizer, or a combination of oral agents on nontraditional risk factors for cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: We randomized 57 patients with T2DM to either (1) continuous subcutaneous basal Lispro insulin at a single rate using an insulin pump (basal insulin) or (2) basal insulin and oral pioglitazone 30 mg daily (basal insulin +Pio) or (3) a sulfonylurea and metformin (SU+M). We measured glycosylated hemoglobin (HbA1c), plasma high-sensitivity C-reactive protein (hs-CRP), plasminogen activator inhibitor-1 (PAI-1), 8-epi-prostaglandin F2 alpha (PGF2alpha), serum lipoprotein (a) [Lp (a)], and lipoprotein profile at baseline and after 20 weeks of treatment. RESULTS: HbA1c decreased by >or=2% (P<.001) and to comparable levels (P=NS) in all groups. Despite improved glycemia, hsCRP did not change in any group, whereas plasma PAI-1 fell with basal insulin +Pio (P<.02) and SU+M (P<.01). PGF2alpha declined with basal insulin (P<.02) and SU+M (P<.001). High-density lipoprotein cholesterol (HDL-C) increased only with basal insulin +Pio (18.2%, P<.05). Lp (a) increased with basal insulin therapy alone (P<.01). Data were pooled from all groups to determine the overall effect of glycemic control-there was a significant (P<.001) decline in HbA1c, PAI-1, and PGF2alpha and an increase in HDL-C (P<.001). There was no correlation between HbA1c reduction and changes in these parameters. CONCLUSIONS: We conclude that excellent glycemic control per se does not impact nontraditional risk factors for CVD equally, but various diabetes medications have different effects on these risk factors. These findings may have implications for making appropriate therapeutic choices for patients with Type 2 diabetes, although larger studies with more appropriate treatment comparisons may be necessary.

    Title Gastric Cancer Risk in a Mexican Population: Role of Helicobacter Pylori Caga Positive Infection and Polymorphisms in Interleukin-1 and -10 Genes.
    Date February 2006
    Journal International Journal of Cancer. Journal International Du Cancer
    Excerpt

    Several polymorphisms of the IL1B and IL10 gene promoters have been reported to be associated with gastric cancer risk in Caucasians. However, studies in other populations have shown differing results. We aimed to test for associations between polymorphisms in IL1B (-31 and +3954), IL10-592 and IL1RN variable number of tandem repeats (VNTR) and risk of gastric cancer in a Mexican population. DNA was extracted from sera of 183 gastric adenocarcinoma patients and 377 controls. The IL1B-31, IL1B+3954 and IL10-592 biallelic polymorphisms were discriminated using 5' Nuclease (TaqMan) assays and Pyrosequencing. The IL1RN penta-allelic VNTR polymorphism was genotyped using PCR followed by GeneScan analysis. A significant interaction was found between IL1B-31 and CagA status for the risk of intestinal-type gastric cancer (p = 0.023). Among CagA positive subjects, those with IL1B-31CC genotype had an increased risk of intestinal-type gastric cancer (OR 3.19, 95%CI = 1.05-9.68), compared to carriers of IL1B-31TT genotype. In contrast, among CagA negative subjects, no significant association of IL1B-31CC genotype with gastric cancer was observed. The IL10-592CC genotype was associated with more than doubling of the risk of the intestinal-type gastric cancer (OR, 2.20, 95%CI = 1.04-4.65). A nonsignificantly increased risk for intestinal-type gastric cancer was found in IL1RN*2 carriers (OR 1.49, 95%CI = 0.89-2.50). None of these polymorphisms was significantly related to the risk of diffuse-type gastric cancer. No significant association was found between risk of gastric cancer and the IL1B+3954 polymorphism. Individuals carrying 2 or more of the risk-associated alleles (IL1B-31C, IL1RN *2 and IL10-592C) were at increased risk for intestinal-type gastric cancer, compared to those with 0 or 1 risk-associated allele. The risk from multiple risk-associated alleles was especially high in subjects infected with CagA positive H. pylori. Our results support the identification of the IL1B-31 promoter polymorphism as a useful marker for risk of intestinal type gastric cancer in persons with CagA positive H. pylori infections.

    Title Effect of a High-carbohydrate Versus a High--cis-monounsaturated Fat Diet on Blood Pressure in Patients with Type 2 Diabetes.
    Date January 2006
    Journal Diabetes Care
    Excerpt

    OBJECTIVE: To investigate whether blood pressure is different in type 2 diabetic patients on a diet rich in carbohydrates versus a diet rich in cis-monounsaturated fatty acids. Data on the dietary effects on these diets' glucose and lipid metabolism have been previously published. RESEARCH DESIGN AND METHODS: The study compared the effect of feeding 42 type 2 diabetic patients a carefully controlled isoenergic high-carbohydrate (high-carb; 55% energy as carbohydrate, 30% as fat, and 10% as monounsaturated fat) and high-monounsaturated fat (high-mono; 45% energy as fat, 25% as monounsaturated fat, and 40% as carbohydrate) diet for 6 weeks each in a four-center, randomized, cross-over study on blood pressure. Twenty-one patients continued the diet they received during the second phase for an additional 8 weeks. RESULTS: According to repeated-measures ANOVA, blood pressure during the last 3 days of each phase was similar after 6 weeks of the high-carb and high-mono diets (systolic blood pressure: 128 +/- 16 vs. 127 +/- 15 mmHg, P = 0.9; diastolic blood pressure: 75 +/- 7 vs. 75 +/- 8 mmHg, P = 0.7). However, after 14 weeks of the high-carb diet (n = 13), there was a significant increase in blood pressure compared with 6 weeks of the high-mono diet (systolic blood pressure: 132 +/- 13 vs. 126 +/- 11 mmHg, P = 0.04; diastolic blood pressure: 83 +/- 6 vs. 76 +/- 7 mmHg, P = 0.002). After 14 weeks of the high-mono diet (n = 8), the reduction in blood pressure was not significant compared with 6 weeks of the high-carb diet (systolic blood pressure: 118 +/- 14 vs. 121 +/- 16 mmHg, P = 0.4; diastolic blood pressure: 71 +/- 8 vs. 75 +/- 10 mmHg, P = 0.3). CONCLUSION: Although the exchange of carbohydrates with monounsaturated fats may not affect blood pressure in the short term, long-term consumption of a high-carbohydrate diet may modestly raise blood pressure in type 2 diabetic patients.

    Title Adipocyte Differentiation-related Protein in Human Skeletal Muscle: Relationship to Insulin Sensitivity.
    Date December 2005
    Journal Obesity Research
    Excerpt

    OBJECTIVE: To determine whether adipocyte differentiation-related protein (ADRP), a lipid droplet-associated protein that binds to and sequesters intracellular fatty acids, is 1) expressed in human skeletal muscle and 2) differentially regulated in human skeletal muscle obtained from obese non-diabetic (OND) and obese diabetic (OD) subjects. RESEARCH METHODS AND PROCEDURES: Ten OND subjects and 15 OD subjects underwent a weight loss or pharmacological intervention program to improve insulin sensitivity. Anthropometric data, hemoglobin A(1C), fasting glucose, lipids, and glucose disposal rate were determined at baseline and at completion of studies. Biopsies of the vastus lateralis muscle (SkM) were obtained in the fasting state from OND and OD subjects. Protein expression was determined by Western blotting. RESULTS: ADRP was highly expressed in SkM from OND (4.4 +/- 1.54 AU/10 microg, protein, n = 10) and OD (5.02 +/- 1.33 AU/10 microg, n = 12) subjects. OND subjects undergoing weight loss had decreased triglyceride levels and improved insulin action. SkM ADRP content increased with weight loss from 5.14 +/- 2.15 AU/10 microg to 9.92 +/- 1.57 AU/10 microg (p < 0.025). OD subjects were treated with either troglitazone or metformin, together with glyburide, for 3 to 4 months. Both treatments attained similar levels of glycemic control. OD subjects with lower baseline ADRP content (2.85 +/- 1.07 AU/10 microg, n = 6) displayed up-regulation of ADRP expression (to 9.27 +/- 2.76 AU/10 microg, p < 0.025). DISCUSSION: ADRP is the predominant lipid droplet-associated protein in SkM, and low ADRP expression is up-regulated in circumstances of improved glucose tolerance. Up-regulation of ADRP may act to sequester fatty acids as triglycerides in discrete lipid droplets that could protect muscle from the detrimental effects of fatty acids on insulin action and glucose tolerance.

    Title Effects of the Rapid-acting Insulin Analog Glulisine on Cultured Human Skeletal Muscle Cells: Comparisons with Insulin and Insulin-like Growth Factor I.
    Date November 2005
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    CONTEXT: The insulin analog LysB3,GluB29-insulin (glulisine) displays accelerated in vivo bioavailability compared with native insulin. OBJECTIVE: Biological properties of this rapid-acting insulin analog were compared with the actions of native insulin and IGF-I. DESIGN: The effects of the hormones on hormone binding, glucose uptake, and thymidine uptake were evaluated in cultured human skeletal muscle cells. SETTING: This study was performed at a Veterans Administration hospital for patient characterization and tissue biopsies; in vitro studies were performed in a research laboratory. PATIENTS OR OTHER PARTICIPANTS: Skeletal muscle tissue was obtained from nondiabetic (n = 13) and type 2 diabetic (n = 14) subjects. INTERVENTION: Cultured skeletal muscle cells were treated acutely (15-90 min) or chronically (16 h) with varying concentrations of hormones. MAIN OUTCOME: The main study outcomes were measures of sensitivity (concentration required to attain 50% displacement of specific [125I]insulin or [125I]IGF-I bound and sensitivity (EC50) and potency (maximal response) for hormone binding and biological responses. RESULTS: Insulin and glulisine were comparable in their ability to displace insulin binding. Neither insulin nor glulisine competed efficiently for IGF-I binding. Insulin, glulisine, and IGF-I were equipotent in the stimulation of glucose uptake. Maximal stimulation of phosphorylation of Akt was greatest for IGF-I, whereas sensitivities were similar to those for glucose uptake. Sensitivities were comparable in muscle cells from nondiabetic and type 2 diabetic subjects. Stimulation of [3H]thymidine uptake was most responsive to IGF-I; insulin and glulisine were equally less effective, with sensitivities approximately 1-2% of that for IGF-I. Stimulation of p42/44 MAPK phosphorylation reflected the behavior of thymidine uptake. CONCLUSIONS: Although altered pharmacokinetics of glulisine can have therapeutic advantages, glulisine is indistinguishable from native insulin at the skeletal muscle level.

    Title Pancreastatin: Multiple Actions on Human Intermediary Metabolism in Vivo, Variation in Disease, and Naturally Occurring Functional Genetic Polymorphism.
    Date October 2005
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    RATIONALE: The chromogranin A (CHGA) fragment pancreastatin (human CHGA250-301) impairs glucose metabolism, but the role of human pancreastatin in vivo remains unexplored. METHODS: We studied brachial arterial infusion of pancreastatin (CHGA273-301-amide at approximately 200 nm) on forearm metabolism of glucose, free fatty acids, and amino acids. Plasma pancreastatin was measured in obesity or type 2 diabetes. Systematic discovery of amino acid variation was performed, and the potency of one variant in the active carboxyl terminus (Gly297Ser) was tested. RESULTS: Pancreastatin decreased glucose uptake by approximately 48-50%; the lack of change in forearm plasma flow indicated a metabolic, rather than hemodynamic, mechanism. A control CHGA peptide (catestatin, CHGA352-372) did not affect glucose. Insulin increased glucose uptake, but pancreastatin did not antagonize this action. Pancreastatin increased spillover of free fatty acids by about 4.5- to 6.4-fold, but not spillover of amino acids. Insulin diminished spillover of both free fatty acids and amino acids, but these actions were not reversed by pancreastatin. Plasma pancreastatin was elevated approximately 3.7-fold in diabetes, but was unchanged during weight loss. Proteolytic cleavage sites for pancreastatin in vivo were documented by matrix-assisted laser desorption ionization/time of flight mass spectrometry. Three pancreastatin variants were discovered: Arg253Trp, Ala256Gly, and Gly297Ser. The Gly297Ser variant had unexpectedly increased potency to inhibit glucose uptake. CONCLUSIONS: The dysglycemic peptide pancreastatin is specifically and potently active in humans on multiple facets of intermediary metabolism, although it did not antagonize insulin. Pancreastatin is elevated in diabetes, and the variant Gly297Ser had increased potency to inhibit glucose uptake. The importance of human pancreastatin in vivo as well as its natural variants is established.

    Title Impaired Fatty Acid Metabolism in Type 2 Diabetic Skeletal Muscle Cells is Reversed by Ppargamma Agonists.
    Date July 2005
    Journal American Journal of Physiology. Endocrinology and Metabolism
    Excerpt

    The impact of type 2 diabetes on the ability of muscle to accumulate and dispose of fatty acids and triglycerides was evaluated in cultured muscle cells from nondiabetic (ND) and type 2 diabetic (T2D) subjects. In the presence of 5 microM palmitate, T2D muscle cells accumulated less lipid than ND cells (11.5 +/- 1.2 vs. 15.1 +/- 1.4 nmol/mg protein, P < 0.05). Chronic treatment (4 days) with the peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist troglitazone increased palmitate accumulation, normalizing uptake in T2D cells. There were no significant differences between groups with regard to the relative incorporation of palmitate into neutral lipid species. This distribution was also unaffected by troglitazone treatment. beta-Oxidation of both long-chain (palmitate) and medium-chain (octanoate) fatty acids in T2D muscle cells was reduced by approximately 40% compared with ND cells. Palmitate oxidation occurred primarily in mitochondrial ( approximately 40-50% of total) and peroxisomal (20-30%) compartments. The diabetes-related defect in palmitate oxidation was localized to the mitochondrial component. Both palmitate and octanoate oxidation were stimulated by a series of thiazolidinediones. Oxidation in T2D muscle cells was normalized after treatment. Troglitazone increased the mitochondrial component of palmitate oxidation. Skeletal muscle cells from T2D subjects express defects in free fatty acid metabolism that are retained in vitro, most importantly defects in beta-oxidation. These defects can be corrected by treatment with PPARgamma agonists. Augmentation of fatty acid disposal in skeletal muscle, potentially reducing intramyocellular triglyceride content, may represent one mechanism for the lipid-lowering and insulin-sensitizing effects of thiazolidinediones.

    Title Combination Therapy for Type 2 Diabetes.
    Date April 2005
    Journal Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
    Excerpt

    To discuss a rational approach to improvement of glycemic control in patients with type 2 diabetes mellitus with use of combination therapy.

    Title Effects of Exenatide (exendin-4) on Glycemic Control over 30 Weeks in Sulfonylurea-treated Patients with Type 2 Diabetes.
    Date March 2005
    Journal Diabetes Care
    Excerpt

    This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy.

    Title Role of Glycemic Control and Protein Restriction in Clinical Management of Diabetic Kidney Disease.
    Date February 2005
    Journal Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
    Excerpt

    OBJECTIVE: To assess the role of control of blood glucose levels and restriction of dietary protein in the management of diabetic nephropathy. METHODS: We summarize the results of pertinent published studies of glycemic control and modification of protein intake to provide information about strategies that potentially could benefit patients with diabetes and renal dysfunction. RESULTS: Considerable evidence is available to support the contention that improved glycemic control may have beneficial effects on the development and progression of diabetic renal disease. Maximal benefits of improved glycemia occur when instituted before the onset of macroalbuminuria. Once overt diabetic nephropathy is established, improved glycemic control may not be beneficial. Current evidence indicates that a glycosylated hemoglobin level of less than 8.1% should be the glycemic goal. At this level, the risk of developing micro-albuminuria is substantially reduced, and the risk of hypoglycemia is minimized. Most studies have been conducted in type I diabetes, and the results have been extrapolated to type II diabetes. Whether improved glycemic control will be equally beneficial in the nephropathy of type II diabetes has yet to be determined. Although some scientific evidence supports dietary protein restriction in patients with diabetic nephropathy, the extent of restriction needed for optimal benefits and minimal side effects remains to be determined. On the basis of current information, patients with both types of diabetes who have evidence of nephropathy should have protein limited to the recommended dietary allowance for adults (0.8 g/kg of body weight per day or approximately 10% of total daily caloric intake), and protein should be derived primarily from vegetable and lean animal sources. CONCLUSION: End-stage renal disease is not inevitable in patients with diabetic nephropathy. Normalization of glucose levels and modification of protein intake can favorably influence the course of diabetes-related kidney disease.

    Title Skeletal Muscle Glut1 Transporter Protein Expression and Basal Leg Glucose Uptake Are Reduced in Type 2 Diabetes.
    Date February 2005
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    To investigate the role of skeletal muscle tissue expression of the glucose transporter protein GLUT1 in mediating glucose disposal in the basal (fasting) state, skeletal muscle biopsies (vastus lateralis) were obtained from lean and obese nondiabetics and type 2 diabetic subjects. Basal and insulin-stimulated glucose uptakes were measured. Basal whole body glucose uptake was measured using isotope dilution, and arteriovenous catheterization limb balance was used to determine leg muscle glucose uptake. Basal (noninsulin-stimulated) whole body glucose uptake was higher in the type 2 group compared with the controls (2.26 +/- 0.17 vs. 1.83 +/- 0.15 mg/kg.min; P < 0.05). However, basal leg muscle glucose uptake was reduced in diabetic subjects (1.53 +/- 0.56 vs. 3.89 +/- 0.83 mg/100 ml.min; P < 0.025) despite basal hyperglycemia (230 +/- 13 vs. 94 +/- 2 mg/dl; P < 0.0005). Skeletal muscle GLUT1 protein expression was lower in the type 2 subjects (57 +/- 12 vs. 91 +/- 11 arbitrary units/10 microg protein; P < 0.05), although GLUT1 mRNA levels did not differ. In summary, 1) skeletal muscle tissue GLUT1 protein expression is reduced in type 2 diabetes and could contribute to impaired basal leg glucose uptake; and 2) elevated rates of basal whole body glucose uptake in type 2 diabetes are due to uptake in tissues other than skeletal muscle.

    Title Diabetes and Obesity: Medical Diseases, Surgical Cure?
    Date February 2005
    Journal Current Diabetes Reports
    Title Prognostic Role of B-type Natriuretic Peptide Levels in Patients with Type 2 Diabetes Mellitus.
    Date September 2004
    Journal Journal of the American College of Cardiology
    Excerpt

    OBJECTIVES: We hypothesized that B-type natriuretic peptide (BNP) levels can predict cardiac mortality in diabetic patients. BACKGROUND: Detection of cardiovascular disease in diabetics can be difficult until overt events occur. METHODS: A total of 482 diabetics (majority male with type 2 diabetes) at the Veterans Affairs Medical Center San Diego were divided into two groups: 1) referred patients for echocardiogram on the basis of clinical suspicion of cardiac dysfunction (referred [R], n = 180); 2) patients randomly selected from the diabetic clinic without any suspicion of cardiac dysfunction (not referred [N-R], n = 302). We examined cardiac events and all-cause mortality in relation to initial BNP levels during the follow-up. RESULTS: A total of 71 (14.7%) patients died during this period: 52 of 180 (29%) in the R group (30 of 52 [58%] cardiac, 10 of 52 [19%] non-cardiac, 2 of 52 [4%] renal, 10 of 52 [19%] unknown cause) and 19 of 302 (6%) in N-R group (6 of 19 [32%] cardiac). The median BNP level in the R and N-R groups who died of cardiac, non-cardiac, and unknown cause was 537 and 87, 80 and 53, and 343 and 38 pg/ml, respectively. The receiver-operating characteristic (ROC) values for mortality in two groups in relation to BNP revealed the area under the curve to be 0.720 and 0.691, respectively (p < 0.01 in both). Among commonly used prognostic indicators in diabetics, only the ROC for triglycerides was significant. The most accurate cut-point in both the N-R group (87%) and R group (61%) was 120 pg/ml of BNP. Cox regression analysis showed BNP to be the most significant predictor of all-cause mortality in the R group. There was a marked decrease in survival in the patient group with BNP >120 pg/ml. CONCLUSIONS: B-type natriuretic peptide appears to be a reliable predictor of future cardiac and all-cause mortality in diabetic patients.

    Title Glitazones and the Management of Insulin Resistance: What They Do and How Might They Be Used.
    Date September 2004
    Journal Endocrinology and Metabolism Clinics of North America
    Excerpt

    Thiazolidinediones (glitazones) are the only compounds currently available that specifically target tissue insulin resistance. The two currently available drugs in this class, pioglitazone and rosiglitazone,are approved by the Food and Drug Administration for the treatment of type 2 diabetes mellitus only. The therapeutic potential of the glitazones for other consequences of insulin resistance has stirred considerable interest, especially with regard to their potential beneficial impact on atherosclerotic cardiovascular disease and diabetes prevention. They also have been considered in the management of polycystic ovarian syndrome, nonalcoholic fatty liver disease, and other consequences of insulin resistance. The nonglycemic potential of glitazones is a clinical area in rapid evolution, wherein most data are on the impact of the glitazones onsurrogate markers that are associated with diseases, not on disease outcomes. This article provides insight and guidance to clinicians on the diverse nonglycemic potential of glitazones until conclusive outcome data become available.

    Title Thiazolidinediones, Peripheral Edema, and Type 2 Diabetes: Incidence, Pathophysiology, and Clinical Implications.
    Date April 2004
    Journal Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
    Excerpt

    To present an objective, evidence-based review of edema associated with thiazolidinedione use in patients with type 2 diabetes.

    Title Hyperglycemia with Antipsychotic Treatment.
    Date March 2004
    Journal Current Diabetes Reports
    Excerpt

    Diabetes and mental disorders are common chronic illnesses in the United States. Recently, the introduction of a new class of atypical antipsychotic medications has been a major treatment advance for patients with mental disorders. Because of increased use of atypical antipsychotic medications, new and unanticipated side effects have often appeared. Treatment-emergent diabetes has been described for conventional and atypical antipsychotics. People with schizophrenia may be at increased risk for type 2 diabetes because of the side effects of antipsychotic medication, underlying predisposition, and less healthy lifestyles.

    Title Young and Elderly Type 2 Diabetic Patients Inhaling Insulin with the Aerx Insulin Diabetes Management System: a Pharmacokinetic and Pharmacodynamic Comparison.
    Date March 2004
    Journal Journal of Clinical Pharmacology
    Excerpt

    The objective of this study was to compare the pharmacokinetics (PK), pharmacodynamics (PD), and safety of inhaled insulin delivered by the AERx iDMS in young and elderly patients with type 2 diabetes. Twenty-seven young (18-45 years, inclusive) and 28 elderly (>/= 65 years) type 2 diabetic patients were enrolled in this study. A single inhalation of 1.57 mg (45 IU, effect comparable to 6 s.c. units) of regular human insulin was administered to each patient on each of 2 dosing days, and blood samples were drawn up to 360 minutes postdosing to generate the PK/PD curves. AUC(0-360 min) and Cmax values of inhaled insulin were comparable between young and elderly subjects (p = 0.476 for AUC(0-360 min) and p = 0.414 for Cmax). However, the elderly group had significantly less glucose reduction, as indicated by plasma glucose AOC(0-360) (area over the curve) values (p = 0.011). The intrasubject variability of inhaled insulin using the AERx iDMS was similar for young and elderly subjects and was similar to what has previously been reported for soluble insulin administered subcutaneously. Inhaled insulin was well tolerated in these patients, and no changes in pulmonary function tests were observed. A single inhalation of insulin using the AERx iDMS demonstrated comparable insulin PK profiles between the elderly and young type 2 patients but less glucose reduction in the elderly. Based on these results, elderly diabetic patients may need to inhale more insulin than young patients to achieve similar glycemic control. Long-term clinical trials using the AERx device will be useful to study age-related differences.

    Title Lack of Effect of Sucralose on Glucose Homeostasis in Subjects with Type 2 Diabetes.
    Date January 2004
    Journal Journal of the American Dietetic Association
    Excerpt

    To investigate the effect of 3-months' daily administration of high doses of sucralose, a non-nutritive sweetener, on glycemic control in subjects with type 2 diabetes.

    Title Evaluation of Insulin Sensitivity in Healthy Volunteers Treated with Olanzapine, Risperidone, or Placebo: a Prospective, Randomized Study Using the Two-step Hyperinsulinemic, Euglycemic Clamp.
    Date January 2004
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    The primary objective of this study was to evaluate insulin sensitivity in healthy subjects treated with olanzapine or risperidone. Subjects were randomly assigned to single-blind therapy with olanzapine (10 mg/d), risperidone (4 mg/d), or placebo for approximately 3 wk. Insulin sensitivity was assessed pre- and posttreatment using a 2-step, hyperinsulinemic, euglycemic clamp. Glucose and insulin responses were also assessed by a mixed meal tolerance test. Of the 64 subjects randomized, 22, 14, and 19 in the olanzapine, risperidone, and placebo groups, respectively, completed the study procedures. There were no significant within-group changes in the glucose disposal rate or the insulin sensitivity index for the active therapy groups. Further, the results of the mixed meal tolerance test did not demonstrate clinically significant changes in integrated glucose metabolism during treatment with these medications. In summary, this study did not demonstrate significant changes in insulin sensitivity in healthy subjects after 3 wk of treatment with olanzapine or risperidone.

    Title Insulin Resistance: from Predisposing Factor to Therapeutic Target in Type 2 Diabetes.
    Date December 2003
    Journal Clinical Therapeutics
    Excerpt

    Insulin resistance contributes to the pathogenesis of type 2 diabetes and is closely linked with cardiovascular risk factors and premature cardiovascular disease.

    Title Adiponectin: More Than Just Another Fat Cell Hormone?
    Date November 2003
    Journal Diabetes Care
    Title Insulin-stimulated Protein Kinase C Lambda/zeta Activity is Reduced in Skeletal Muscle of Humans with Obesity and Type 2 Diabetes: Reversal with Weight Reduction.
    Date September 2003
    Journal Diabetes
    Excerpt

    In humans with obesity or type 2 diabetes, insulin target tissues are resistant to many actions of insulin. The atypical protein kinase C (PKC) isoforms lambda and zeta are downstream of phosphatidylinositol-3 kinase (PI3K) and are required for maximal insulin stimulation of glucose uptake. Phosphoinositide-dependent protein kinase-1 (PDK-1), also downstream of PI3K, mediates activation of atypical PKC isoforms and Akt. To determine whether impaired PKClambda/zeta or PDK-1 activation plays a role in the pathogenesis of insulin resistance, we measured the activities of PKClambda/zeta and PDK-1 in vastus lateralis muscle of lean, obese, and obese/type 2 diabetic humans. Biopsies were taken after an overnight fast and after a 3-h hyperinsulinemic-euglycemic clamp. Obese subjects were also studied after weight loss on a very-low-calorie diet. Insulin-stimulated glucose disposal rate is reduced 26% in obese subjects and 62% in diabetic subjects (both comparisons P < 0.001). Insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and PI3K activity are impaired 40-50% in diabetic subjects compared with lean or obese subjects. Insulin stimulates PKClambda/zeta activity approximately 2.3-fold in lean subjects; the increment above basal is reduced 57% in obese and 65% in diabetic subjects. PKClambda/zeta protein amount is decreased 46% in diabetic subjects but is normal in obese nondiabetic subjects, indicating impaired insulin action on PKClambda/zeta. Importantly, weight loss in obese subjects normalizes PKClambda/zeta activation and increases IRS-1 phosphorylation and PI3K activity. Insulin also stimulates PDK-1 activity approximately twofold with no impairment in obese or diabetic subjects. In contrast to our previous data on Akt, reduced insulin-stimulated PKClambda/zeta activity could play a role in the pathogenesis of insulin resistance in muscle of obese and type 2 diabetic subjects.

    Title Inhaled Insulin Using the Aerx Insulin Diabetes Management System in Healthy and Asthmatic Subjects.
    Date September 2003
    Journal Diabetes Care
    Excerpt

    OBJECTIVE: The AERx insulin Diabetes Management System (AERx iDMS) (Aradigm, Hayward, CA) delivers an aerosol of liquid human insulin to the deep lung for systemic absorption. This study examined the effects on pulmonary function, pharmacokinetics, and pharmacodynamics of inhaled insulin in asthmatic and nonasthmatic subjects without diabetes. RESEARCH DESIGN AND METHODS: A total of 28 healthy and 17 asthmatic (forced expiratory volume during the first second [ FEV(1)] 50-80% of predicted value) subjects were enrolled in a two-part, open-label trial. To assess insulin pharmacokinetics and pharmacodynamics, a single inhalation dose of 1.57 mg (45 IU) was given on each of the 2 dosing days in part 1. A dose of 4.7 mg (135 IU) of insulin was inhaled in part 2 to assess effects on pulmonary function. RESULTS: Inhaled insulin showed area under the curve (AUC)((0-360 min)) values that were significantly greater for healthy subjects than for asthmatic subjects (P = 0.013), whereas no difference was observed for maximum concentration (C(max)) in the two groups. A greater reduction of serum glucose as indicated by area over the curve (AOC)((0-360 min)) was observed in healthy subjects (P = 0.007). Asthmatic subjects had greater intrasubject variations in insulin AUC((0-360 min)) and C(max) values than healthy subjects, but similar variations in glucose AOC((0-360 min)). No significant changes in FEV(1), forced vital capacity (FVC), and FEV(1)/FVC were observed from pre- to postdose times, and there were no observed safety issues. CONCLUSIONS: After inhaling insulin using the AERx iDMS, asthmatic subjects absorbed less insulin than healthy subjects, resulting in less reduction of serum glucose. No effects on airway reactivity were observed. Diabetic patients with asthma may need to inhale more insulin than patients with normal respiratory function in order to achieve similar glycemic control.

    Title Thiazolidinediones Upregulate Impaired Fatty Acid Uptake in Skeletal Muscle of Type 2 Diabetic Subjects.
    Date August 2003
    Journal American Journal of Physiology. Endocrinology and Metabolism
    Excerpt

    We examined the regulation of free fatty acid (FFA, palmitate) uptake into skeletal muscle cells of nondiabetic and type 2 diabetic subjects. Palmitate uptake included a protein-mediated component that was inhibited by phloretin. The protein-mediated component of uptake in muscle cells from type 2 diabetic subjects (78 +/- 13 nmol. mg protein-1. min-1) was reduced compared with that in nondiabetic muscle (150 +/- 17, P < 0.01). Acute insulin exposure caused a modest (16 +/- 5%, P < 0.025) but significant increase in protein-mediated uptake in nondiabetic muscle. There was no significant insulin effect in diabetic muscle (+19 +/- 19%, P = not significant). Chronic (4 day) treatment with a series of thiazolidinediones, troglitazone (Tgz), rosiglitazone (Rgz), and pioglitazone (Pio) increased FFA uptake. Only the phloretin-inhibitable component was increased by treatment, which normalized this activity in diabetic muscle cells. Under the same conditions, FFA oxidation was also increased by thiazolidinedione treatment. Increases in FFA uptake and oxidation were associated with upregulation of fatty acid translocase (FAT/CD36) expression. FAT/CD36 protein was increased by Tgz (90 +/- 22% over control), Rgz (146 +/- 42%), and Pio (111 +/- 37%, P < 0.05 for all 3) treatment. Tgz treatment had no effect on fatty acid transporter protein-1 and membrane-associated plasmalemmal fatty acid-binding protein mRNA expression. We conclude that FFA uptake into cultured muscle cells is, in part, protein mediated and acutely insulin responsive. The basal activity of FFA uptake is impaired in type 2 diabetes. In addition, chronic thiazolidinedione treatment increased FFA uptake and oxidation into cultured human skeletal muscle cells in concert with upregulation of FAT/CD36 expression. Increased FFA uptake and oxidation may contribute to lower circulating FFA levels and reduced insulin resistance in skeletal muscle of individuals with type 2 diabetes following thiazolidinedione treatment.

    Title Regulation of Skeletal Muscle Morphology in Type 2 Diabetic Subjects by Troglitazone and Metformin: Relationship to Glucose Disposal.
    Date June 2003
    Journal Metabolism: Clinical and Experimental
    Excerpt

    The goal of this work was to compare the effects of different antidiabetic therapies on the phenotype of skeletal muscle in type 2 diabetic subjects failing sulfonylurea therapy. Subjects were treated with a thiazolidinedione (troglitazone, TGZ) or a biguanide (metformin, MET) in addition to glyburide for 3 to 4 months. Insulin action was determined with a hyperinsulinemic (300 mU. m(-2). min(-1)) euglycemic (5.0 to 5.5 mmol/L) clamp. Biopsies were obtained from the vastus lateralis muscle for morphological analysis. Despite similar glycemic control, relative increases in the insulin-stimulated glucose disposal rate (GDR) were greater after TGZ treatment (37 +/- 8% increase, P <.05) than after MET (21 +/- 11%, P <.05). Neither treatment had any effect on fiber type composition of the muscle. Capillary density was reduced in diabetic subjects compared to a nondiabetic group (P <.01) and was increased with TGZ treatment (P <.05), while MET was without significant effect. Diabetic muscle also displayed a lower mitochondrial volume density that was unaltered by either treatment. Both TGZ and MET therapy resulted in a reduction in the lipid content of muscle (percent fiber volume as lipid droplets); the relative decrease tended to be greater for TGZ (-33% v -23% for MET). The relative (%) improvement in GDR was correlated with the change in lipid content (r = -0.756, P <.05) after TGZ treatment; no such relationship was observed for MET. From these results we conclude that the higher potency of TGZ to increase capillary density and reduce the lipid content of muscle may contribute to its greater ability to improve glucose disposal in skeletal muscle of type 2 diabetic individuals.

    Title Impact of Pramlintide on Glucose Fluctuations and Postprandial Glucose, Glucagon, and Triglyceride Excursions Among Patients with Type 1 Diabetes Intensively Treated with Insulin Pumps.
    Date June 2003
    Journal Diabetes Care
    Excerpt

    OBJECTIVE: To assess the effects of adjunctive treatment with pramlintide, an analog of the beta-cell hormone amylin, on 24-h glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions in patients with type 1 diabetes intensively treated with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: In this study, 18 patients (16 of whom could be evaluated) with type 1 diabetes (age 44 +/- 11 years, HbA(1c) 8.2 +/- 1.3% [mean +/- SD]) were given mealtime injections of 30 micro g pramlintide t.i.d. for 4 weeks in addition to their preexisting CSII regimen (16 lispro, 2 regular insulin). Mealtime insulin boluses were reduced by a minimum of 10% during the first 3 days, and re-adjusted thereafter based on clinical judgment. At weeks 0 (baseline), 4 (on treatment), and 6 (2 weeks off treatment), 24-h interstitial glucose concentrations were measured using a continuous glucose monitoring system (CGMS), and postprandial plasma glucose, glucagon, and triglyceride concentrations were measured in response to a standardized test meal. RESULTS: At baseline, patients had excessive 24-h glucose fluctuations, with 59% of the CGMS measurements >140 mg/dl, 13% <80 mg/dl, and only 28% in the euglycemic range (80-140 mg/dl). After 4 weeks on pramlintide, measurements in the hyperglycemic range declined to 48% and measurements within the euglycemic range increased to 37%. This shift from the hyperglycemic to the euglycemic range occurred with a concomitant 17% reduction in mealtime insulin dosages and without relevant increases in measurements below the euglycemic range (15%) or any severe hypoglycemic events. After 4 weeks on pramlintide, postprandial glucose, glucagon, and triglyceride excursions were reduced by approximately 86, approximately 87, and approximately 72%, respectively (incremental areas under the curve, all P < 0.05 vs. baseline). At week 6 (off treatment), the 24-h glucose profile and postprandial glucose, glucagon, and triglyceride excursions approached pretreatment values. CONCLUSIONS: In this study, the addition of pramlintide to insulin therapy reduced excessive 24-h glucose fluctuations as well as postprandial glucose, glucagon, and triglyceride excursions in patients with type 1 diabetes intensively treated with insulin pumps.

    Title Modulation of Circulating and Adipose Tissue Adiponectin Levels by Antidiabetic Therapy.
    Date May 2003
    Journal Diabetes
    Excerpt

    The relationship between insulin action and control of the adipocyte-derived factor adiponectin was studied in age- and weight-matched obese individuals with type 2 diabetes failing sulfonylurea therapy. After initial metabolic characterization, subjects were randomized to troglitazone or metformin treatment groups; all subjects received glyburide (10 mg BID) as well. Treatment was continued for 3 months. The extent of glycemic control after treatment was similar in both groups. However, the increase in maximal insulin-stimulated glucose disposal rate was greater following troglitazone therapy (+44%) compared with metformin treatment (+20%). Troglitazone treatment increased serum adiponectin levels nearly threefold. There was no change in serum adiponectin with metformin treatment. A positive correlation was found between increases in whole-body glucose disposal rates and serum adiponectin levels after troglitazone; no such relationship was seen with metformin. The adiponectin protein content of subcutaneous abdominal adipocytes was increased following troglitazone treatment and unchanged after metformin. Adiponectin release from adipocytes was also augmented with troglitazone treatment. Adiponectin was present in adipocytes and plasma in several multimeric forms; a trimer was the major form secreted from adipocytes. These results indicate that increases in adiponectin content and secretion are associated with improved insulin action but are not directly related to glycemic control. Modulation of adipocyte function, including upregulation of adiponectin synthesis and secretion, may be an important mechanism by which thiazolidinediones influence insulin action.

    Title Preventing Diabetes by Treating Aspects of the Metabolic Syndrome.
    Date April 2003
    Journal Current Diabetes Reports
    Excerpt

    The metabolic syndrome often develops into and is usually present in type 2 diabetes in association with premature cardiovascular disease. Treating diabetes can prevent some of its devastating consequences, but it does not eliminate them all. With the goal to eliminate all the adverse consequences of the syndrome, the optimal approach would be through its prevention. Insulin resistance appears to be pivotal to development of the syndrome complex that includes features such as intra-abdominal or visceral obesity, hypertension, impaired glucose homeostasis, dyslipidemia with elevated triglycerides and low high-density lipoprotein without elevations of low-density lipoprotein, a procoagulant state, and impaired vascular function. Improving the insulin resistance needs to be the primary target of the therapy. Hyperglycemia, which is one feature of the metabolic syndrome, may range from impaired glucose tolerance (IGT) to overt diabetes. The risk of progression of the disease from IGT to diabetes is increased with time and the presence of various risk factors. Diabetes is a disease of serious concern because of the associated complication of the disease and the huge impact on the health care costs. Many short- and longer-term trials have shown promise in the prevention of diabetes and its metabolic and cardiovascular consequences.

    Title Intravenous Glargine and Regular Insulin Have Similar Effects on Endogenous Glucose Output and Peripheral Activation/deactivation Kinetic Profiles.
    Date February 2003
    Journal Diabetes Care
    Excerpt

    To compare the effects of intravenously administered long-acting insulin analog glargine and regular human insulin on activation and deactivation of endogenous glucose output (EGO) and peripheral glucose uptake.

    Title Insulin and Insulin-like Growth Factor-1 Action on Human Skeletal Muscle: Preferential Effects of Insulin-like Growth Factor-1 in Type 2 Diabetic Subjects.
    Date September 2002
    Journal Metabolism: Clinical and Experimental
    Excerpt

    The metabolic actions of insulin and insulin-like growth factor-1 (IGF-1) were compared in cultured skeletal muscle cells from nondiabetic (ND) and type 2 diabetic subjects. Insulin stimulated glucose uptake with comparable sensitivity in ND (EC(50) = 2.0 +/- 0.7 nmol/L) and diabetic (1.3 +/- 0.4) cells. IGF-1 sensitivity for uptake stimulation was similar in ND (EC(50) = 0.30 +/- 0.06 nmol/L) and type 2 cells (0.37 +/- 0.01). In ND cells, insulin and IGF-1 were equally potent for stimulation of glucose uptake and glycogen synthase (GS) activity. However, in diabetic cells, maximal insulin stimulation of both responses was only half of the increases due to IGF-1. Final absolute activities after IGF-1 stimulation were still lower in diabetic cells compared with cells from ND subjects. Hormonal stimulation of Akt phosphorylation exhibited the same behavior as metabolic responses; comparable for insulin and IGF-1 in ND muscle, while IGF-1 was significantly more effective in diabetic cells. Both insulin receptor (IR) binding and receptor protein expression were similar in ND and diabetic cells. IGF-1 binding and receptor protein expression were not significantly different in diabetic compared with ND cells. The expression of IGF-binding proteins (IGFBP) 3, 5, and 6 were similar in ND and diabetic cells; IGFBP-4 was slightly, but significantly higher, in diabetic cells. While insulin and IGF-1 are equally effective on metabolic responses in ND muscle, diabetic muscle cells are markedly more resistant to insulin than IGF-1. The greater metabolic activity of IGF-1 in type 2 diabetic muscle may provide new insights into the mechanisms of insulin resistance in skeletal muscle.

    Title Free Fatty Acid Metabolism in Human Skeletal Muscle is Regulated by Ppargamma and Rxr Agonists.
    Date August 2002
    Journal Annals of the New York Academy of Sciences
    Excerpt

    Free fatty acid (FFA) oxidation in human skeletal muscle cells can be stimulated, both independently and in a synergistic manner, by agonists for PPARgamma and RXR. Increased FFA disposal in muscle through augmented oxidation could reduce intramyocellular lipid accumulation. The abilities of such agents to improve glucose tolerance and insulin action may thus involve effects on both glucose and FFA metabolism.

    Title Inhibition of Glycogen Synthase Kinase 3 Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle.
    Date July 2002
    Journal Diabetes
    Excerpt

    Glycogen synthase kinase (GSK)-3 has been implicated in the regulation of multiple cellular physiological processes in skeletal muscle. Selective cell-permeable reversible inhibitors (INHs) of GSK-3 (CT98014 and CHIR98023 [Chiron, Emeryville, CA] and LiCl) were used to evaluate the role of GSK-3 in controlling glucose metabolism. Acute treatment (30 min) of cultured human skeletal muscle cells with either INH resulted in a dose-dependent activation of glycogen synthase (GS) with a maximally effective concentration of approximately 2 micromol/l. The maximal acute effect of either INH on GS (103 +/- 25% stimulation over basal) was greater than the maximal insulin response (48 +/- 9%, P < 0.05 vs. INH); LiCl was as effective as insulin. The GSK-3 inhibitor effect, like that of insulin, was on the activation state (fractional velocity [FV]) of GS. Cotreatment of muscle cells with submaximal doses of INH and insulin resulted in an additive effect on GS FV (103 +/- 10% stimulation, P < 0.05 vs. either agent alone). Glucose incorporation into glycogen was also acutely stimulated by INH. While prolonged (6-24 h) insulin exposure led to desensitization of GS, INH continued to activate GS FV for at least 24 h. Insulin and LiCl acutely activated glucose uptake, whereas INH stimulation of glucose uptake required more prolonged exposure, starting at 6 h and continuing to 24 h. Chronic (4-day) treatment with INH increased both basal (154 +/- 32% of control) and insulin-stimulated (219 +/- 74%) glucose uptake. Upregulation of uptake activity occurred without any change in total cellular GLUT1 or GLUT4 protein content. Yet the same chronic treatment resulted in a 65 +/- 6% decrease in GSK-3 protein and a parallel decrease (61 +/- 11%) in GSK-3 total activity. Together with the INH-induced increase in insulin-stimulated glucose uptake, there was an approximately 3.5-fold increase (P < 0.05) in insulin receptor substrate (IRS)-1 protein abundance. Despite upregulation of IRS-1, maximal insulin stimulation of Akt phosphorylation was unaltered by INH treatment. The results suggest that selective inhibition of GSK-3 has an impact on both GS and glucose uptake, including effects on insulin action, using mechanisms that differ from and are additive to those of insulin.

    Title Role of Glycogen Synthase Kinase-3 in Skeletal Muscle Insulin Resistance in Type 2 Diabetes.
    Date May 2002
    Journal Journal of Diabetes and Its Complications
    Title Differential Effects of Metformin and Troglitazone on Cardiovascular Risk Factors in Patients with Type 2 Diabetes.
    Date May 2002
    Journal Diabetes Care
    Excerpt

    OBJECTIVE: Traditional cardiovascular risk factors (CVRF) only partly explain the excessive risk of cardiovascular disease in patients with type 2 diabetes. There is now an increasing appreciation for many novel CVRF that occur largely as a result of insulin resistance and hyperinsulinemia. Therefore, we investigated whether diabetes medications that vary in their mechanism of action and ability to reduce insulin resistance may differ in their effects on both traditional and novel CVRF. RESEARCH DESIGN AND METHODS: We compared the addition of metformin or troglitazone therapy on CVRF in 22 subjects with type 2 diabetes who remained in poor glycemic control (with HbA1c >8.5%) while taking glyburide 10 mg twice daily. Subjects were initially randomized to either metformin 850 mg once daily or troglitazone 200 mg once daily. Both medications were then titrated upward as needed to achieve fasting plasma glucose <120 mg/dl. Measures of glucose control, insulin resistance, and CVRF (blood pressure, lipids, plasminogen activator inhibitor-1, C-reactive protein, fibrinogen, and small dense LDL) were assessed both before and after therapy. RESULTS: After 4 months of treatment, both metformin and troglitazone led to similar decreases in fasting plasma glucose and HbA1c. The reduction in insulin resistance determined by hyperinsulinemic-euglycemic clamp was nearly twofold greater with troglitazone than metformin. Metformin did not induce significant changes in blood pressure, LDL cholesterol, LDL size, HDL cholesterol, triglycerides, or plasminogen activator inhibitor-1. However, C-reactive protein did decrease by 33% (6 +/- 1 to 4 +/- 1 mg/l; P < 0.01) [corrected]. Troglitazone therapy was associated with increases in LDL size (26.21 +/- 0.22 to 26.56 +/- 0.25 nm; P=0.04) and HDL cholesterol (33 +/- 3 to 36 +/- 3 mg/dl; P=0.05) and decreases in triglycerides (197 +/- 19 to 155 +/- 23 mg/dl; P=0.07) and C-reactive protein by 60% (8 +/- 3 to 3 +/- 1 mg/l, P < 0.01) [corrected]. CONCLUSIONS: For patients with type 2 diabetes in whom maximal sulfonylurea therapy failed, the addition of the insulin sensitizer troglitazone seemed to have greater benefits on several traditional and novel CVRF than metformin therapy. These differences were not related to glycemic improvement but reflected, in part, the greater reduction in insulin resistance obtained with addition of troglitazone. These data suggest that medications that more effectively address this underlying metabolic defect may be more beneficial in reducing cardiovascular risk in type 2 diabetes.

    Title Verbal Working Memory Storage and Processing Deficits in Hiv-1 Asymptomatic and Symptomatic Individuals.
    Date March 2002
    Journal Psychological Medicine
    Excerpt

    Verbal working memory (WM), which relies on intact functioning of frontostriatal circuits, has been suggested as a cognitive domain that is preferentially affected in HIV-1 infection. Although several studies have found WM impairments in HIV-1 infected patients, Baddeley's classic WM model has not been studied extensively in this population.

    Title Troglitazone but Not Metformin Restores Insulin-stimulated Phosphoinositide 3-kinase Activity and Increases P110beta Protein Levels in Skeletal Muscle of Type 2 Diabetic Subjects.
    Date March 2002
    Journal Diabetes
    Excerpt

    Insulin stimulation of phosphatidylinositol (PI) 3-kinase activity is defective in skeletal muscle of type 2 diabetic individuals. We studied the impact of antidiabetic therapy on this defect in type 2 diabetic subjects who failed glyburide treatment by the addition of troglitazone (600 mg/day) or metformin (2,550 mg/day) therapy for 3-4 months. Improvement in glycemic control was similar for the two groups, as indicated by changes in fasting glucose and HbA(1c) levels. Insulin action on whole-body glucose disposal rate (GDR) was determined before and after treatment using the hyperinsulinemic (300 mU x m(-2) x min(-1)) euglycemic (5.0-5.5 mmol/l) clamp technique. Needle biopsies of vastus lateralis muscle were obtained before and after each 3-h insulin infusion. Troglitazone treatment resulted in a 35 +/- 9% improvement in GDR (P < 0.01), which was greater than (P < 0.05) the 22 +/- 13% increase (P < 0.05) after metformin treatment. Neither treatment had any effect on basal insulin receptor substrate-1 (IRS-1)-associated PI 3-kinase activity in muscle. However, insulin stimulation of PI 3-kinase activity was augmented nearly threefold after troglitazone treatment (from 67 +/- 22% stimulation over basal pre-treatment to 211 +/- 62% post-treatment, P < 0.05), whereas metformin had no effect. The troglitazone effect on PI 3-kinase activity was associated with a 46 +/- 22% increase (P < 0.05) in the amount of the p110beta catalytic subunit of PI 3-kinase. Insulin-stimulated Akt activity also increased after troglitazone treatment (from 32 +/- 8 to 107 +/- 32% stimulation, P < 0.05) but was unchanged after metformin therapy. Protein expression of other key insulin signaling molecules (IRS-1, the p85 subunit of PI 3-kinase, and Akt) was unaltered after either treatment. We conclude that the mechanism for the insulin-sensitizing effect of troglitazone, but not metformin, involves enhanced PI 3-kinase pathway activation in skeletal muscle of obese type 2 diabetic subjects.

    Title Effect of Pravastatin-to-simvastatin Conversion on Low-density-lipoprotein Cholesterol.
    Date February 2002
    Journal American Journal of Health-system Pharmacy : Ajhp : Official Journal of the American Society of Health-system Pharmacists
    Excerpt

    The effects of a pravastatin-to-simvastatin conversion program on low-density-lipoprotein (LDL) cholesterol levels were studied. Patients receiving pravastatin at a Veterans Affairs medical center were switched to simvastatin beginning in 1997. The dosage of simvastatin was based on the additional percent reduction in LDL cholesterol needed to achieve the goal specified by the National Cholesterol Education Program. The primary endpoint was the change in the percentage of patients meeting their LDL cholesterol goal at baseline and follow-up. Changes in lipid indices, the relative risk (RR) of coronary heart disease (CHD), and program costs were also evaluated. A total of 1032 patients completed the program. The mean +/- S.D. daily doses of pravastatin and simvastatin were 25.2 +/- 11.3 and 22.7 +/- 13.3 mg, respectively. Median baseline and follow-up LDL cholesterol concentrations were 116 and 99 mg/dL, respectively (p < 0.001). Overall, 44% of the patients met their LDL cholesterol goal while taking pravastatin, compared with 69% after conversion to simvastatin (p < 0.001). The predicted mean RR of a future CHD event (based on changes in serum lipids) was 0.87 (95% confidence interval, 0.83-0.91) four years after conversion. The total cost of the program was $40,644 in the first year, and there was a net saving thereafter. Therapeutic interchange between pravastatin and simvastatin increased the number of patients meeting their LDL cholesterol goal.

    Title Regulation of Glucose Transport and Insulin Signaling by Troglitazone or Metformin in Adipose Tissue of Type 2 Diabetic Subjects.
    Date February 2002
    Journal Diabetes
    Excerpt

    Type 2 diabetic subjects failing glyburide therapy were randomized to receive additional therapy with either metformin (2,550 mg/day) or troglitazone (600 mg/day) for 3-4 months. Biopsies of subcutaneous abdominal adipose tissue were obtained before and after therapy. Glycemic control was similar with both treatments. Metformin treatment increased insulin-stimulated whole-body glucose disposal rates by 20% (P < 0.05); the response to troglitazone was greater (44% increase, P < 0.01 vs. baseline, P < 0.05 vs. metformin). Troglitazone-treated subjects displayed a tendency toward weight gain (5 +/- 2 kg, P < 0.05), increased adipocyte size, and increased serum leptin levels. Metformin-treated subjects were weight-stable, with unchanged leptin levels and reduced adipocyte size (to 84 +/- 4% of control, P < 0.005). Glucose transport in isolated adipocytes from metformin-treated subjects was unaltered from pretreatment. Glucose transport in both the absence (321 +/- 134% of pre-Rx, P < 0.05) and presence of insulin (418 +/- 161%, P < 0.05) was elevated after troglitazone treatment. Metformin treatment had no effect on adipocyte content of GLUT1 or GLUT4 proteins. After troglitazone treatment, GLUT4 protein expression was increased twofold (202 +/- 42%, P < 0.05). Insulin-stimulated serine phosphorylation of Akt was augmented after troglitazone (170 +/- 34% of pre-Rx response, P < 0.05) treatment and unchanged by metformin. We conclude that the ability of troglitazone to upregulate adipocyte glucose transport, GLUT4 expression, and insulin signaling can contribute to its greater effect on whole-body glucose disposal.

    Title Effects of the Long-acting Insulin Analog Insulin Glargine on Cultured Human Skeletal Muscle Cells: Comparisons to Insulin and Igf-i.
    Date December 2001
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    The aim of this study was to determine whether the long-acting insulin analog, insulin glargine, behaves like human insulin for metabolic and mitogenic responses in differentiated cultured human skeletal muscle cells from nondiabetic and diabetic subjects. Human insulin and insulin glargine were equipotent in their ability to compete for [(125)I]insulin binding. Insulin glargine displaced [(125)I]IGF-I from the IGF-I-binding site with approximately 0.5% the potency of IGF-I. In nondiabetic muscle cells, all three ligands stimulated glucose uptake similarly, whereas the sensitivity of glucose uptake was greatest in response to IGF-I and lower and equal for human insulin and insulin glargine. In diabetic muscle cells, the final responsiveness of glucose uptake was greatest for IGF-I and equivalent for human insulin and insulin glargine; sensitivities were the same as those for nondiabetic cells. Thymidine uptake into DNA was stimulated foremost by IGF-I, whereas human insulin and insulin glargine showed equivalent, but greatly reduced, sensitivities and potencies (<1% IGF-I). Stimulation of Akt phosphorylation was slightly more responsive to IGF-I compared with human insulin and insulin glargine, with sensitivities similar to glucose uptake stimulation. We conclude that in human skeletal muscle cells, insulin glargine is equivalent to human insulin for metabolic responses and does not display augmented mitogenic effects.

    Title Effects of Home Environment, Socioeconomic Status, and Health Status on Cognitive Functioning in Children with Hiv-1 Infection.
    Date October 2001
    Journal Journal of Pediatric Psychology
    Excerpt

    To investigate the effects of the home environment, socioeconomic status (SES), and health status on cognitive functioning in a sample of children with HIV-1 infection in a cross-sectional study.

    Title Impaired Muscle Glycogen Synthase in Type 2 Diabetes is Associated with Diminished Phosphatidylinositol 3-kinase Activation.
    Date October 2001
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    Insulin signaling pathways potentially involved in regulation of skeletal muscle glycogen synthase were compared in differentiated human muscle cell cultures from nondiabetic and type 2 diabetic patients. Insulin stimulation of glycogen synthase activity as well as phosphorylation of MAPK, p70 S6 kinase, and protein kinase B (Akt) were blocked by the phosphatidylinositol 3-kinase inhibitors wortmannin (50 nM) and LY294002 (10 microM). In contrast to lean and obese nondiabetic subjects, where there were minimal effects (15-20% inhibition), insulin stimulation of glycogen synthase in muscle cultures from diabetic subjects was greatly diminished ( approximately 75%) by low concentrations of wortmannin (25 nM) or LY294002 (2 microM). This increased sensitivity of diabetic muscle to impairment of insulin-stimulated glycogen synthase activity occurs together with diminished insulin-stimulation (by 40%) of IRS-1-associated phosphatidylinositol 3-kinase activity in the same cells. Protein expression of IRS-1, p85, p110, Akt, p70 S6 kinase, and MAPK were normal in diabetic cells, as was insulin-stimulated phosphorylation of Akt, p70 S6 kinase, and MAPK. These studies indicate that, despite prolonged growth and differentiation of diabetic muscle under normal metabolic culture conditions, defects of insulin-stimulated phosphatidylinositol 3-kinase and glycogen synthase activity in diabetic muscle persist, consistent with intrinsic (rather than acquired) defects of insulin action.

    Title Peroxisome Proliferator-activated Receptor (ppar) Gamma and Retinoid X Receptor (rxr) Agonists Have Complementary Effects on Glucose and Lipid Metabolism in Human Skeletal Muscle.
    Date October 2001
    Journal Diabetologia
    Excerpt

    AIMS/HYPOTHESIS: To determine the independent and potentially synergistic effects of agonists for PPAR gamma and RXR on glucose and lipid metabolism, as well as gene expression, in human skeletal muscle cell cultures. METHODS: Fully differentiated myotubes from non-diabetic subjects and subjects with Type II (non-insulin-dependent) diabetes mellitus were chronically (2 days) treated with LG100268 (4 mumol/l), an RXR agonist, or troglitazone (4.6 mumol/l), a PPAR gamma agonist or both, to determine the effects on glucose uptake, activity of glycogen synthase and palmitate oxidation. RESULTS: The combination of both agents increased glucose uptake (60 +/- 9% compared to control subjects) but not either agent alone (16 +/- 9 and 26 +/- 6% for LG100268 and troglitazone, p < 0.01, respectively). The agent LG100268 alone had little effect on the activity of glycogen synthase but the effect of troglitazone increased with LG100268 (p < 0.05). With chronic exposure, LG100268 upregulated palmitate oxidation (53 +/- 12% increase, p < 0.005), in a way similar to troglitazone (68 +/- 23%, p < 0.005). Synergism was observed when both agonists were combined (146 +/- 38%, p < 0.005 vs either agent alone). Treatment with either agent led to about a twofold increase in the expression of fatty acid transporter (FAT/CD36). Troglitazone upregulated PPAR gamma protein expression, whereas LG100268 had no effect. Furthermore, neither LG100268 nor troglitazone had any effect on the protein expression of RXR isoforms or PPAR alpha. CONCLUSION/INTERPRETATION: Co-activation of PPAR gamma and RXR results in additive or synergistic effects on glucose and lipid metabolism in skeletal muscle, but unlike troglitazone, LG100268 does not alter expression of its own receptor.

    Title Pharmacodynamic and Pharmacokinetic Properties of a Premixed 85/15 Human Insulin Preparation.
    Date August 2001
    Journal Clinical Therapeutics
    Excerpt

    BACKGROUND: Many patients with diabetes use mixtures of fast-acting (regular human) insulin and intermediate-acting (neutral protamine Hagedorn [NPH]) insulin to control their blood glucose levels. Premixed insulin is available in a 70%/30% mixture and a 50%/50% mixture of NPH/regular human insulin. For some patients, however, a premixed formulation containing > or =30% regular human insulin can provide too much fast-acting insulin, potentially causing an increased risk for hypoglycemia in the early hours after injection. OBJECTIVE: The pharmacokinetic and pharmacodynamic properties of a premixed formulation of 85% NPH insulin and 15% regular human insulin (85/15) were compared with those of a premixed 70%/30% NPH/regular human insulin preparation and 100% NPH insulin. METHODS: A 12-hour euglycemic clamp approach was used to assess glucose-lowering effects and serum insulin levels in 36 healthy male volunteers in a single-dose (0.5 U/kg), randomized, double-blind, 3-period, crossover study. RESULTS: From 0 to 8 hours after injection, the glucose-lowering effects and serum insulin levels for the 85/15 premixed insulin preparation were significantly greater than those for NPH insulin (P < or = 0.05) but significantly less than those for the 70/30 premixed insulin preparation. The mean (+/- SEM) maximum glucose infusion rate (GIRmax) was 8+/-0.6 mg/(min x kg) for the 85/15 preparation, 7+/-0.6 mg/(min x kg) for NPH, and 9+/-0.6 mg/(min x kg) for the 70/30 preparation, with time to peak GIR (tmax(GIR)) occurring at 313, 360, and 272 minutes, respectively. Time to peak insulin levels did not differ significantly for the 3 preparations, but maximum serum insulin concentration (Cmax(ins)) was significantly different between the groups (70/30 premix: 54+/-2.2 microU/mL; 85/15 premix: 44+/-2.4 microU/mL; NPH: 35+/-1.7 microU/mL). Glucodynamic effect and serum insulin levels did not differ significantly among preparations during the interval from 8 to 12 hours after injection. Mean serum C-peptide levels ranged from -0.6 to 1.0 ng/mL for each preparation during the 12-hour period after injection. CONCLUSIONS: The 85/15 premixed insulin preparation demonstrated clinical pharmacokinetic and pharmacodynamic properties that were intermediate between, and significantly different from, those of NPH insulin and the 70/30 premixed insulin preparation.

    Title Retinoid X Receptor Expression in Skeletal Muscle of Nondiabetic, Obese and Type 2 Diabetic Individuals.
    Date August 2001
    Journal Metabolism: Clinical and Experimental
    Excerpt

    Retinoid X receptor (RXR) is a nuclear receptor that functions as an obligate heterodimeric partner of peroxisome proliferator-activator receptor (PPAR). Studies have shown that the alpha isoform of RXR and PPARgamma act synergistically to regulate gene expression and insulin action. The aim of the current study was to compare the expression and regulation of RXR in the primary insulin-sensitive tissue, skeletal muscle, of various degrees of insulin-resistant states including obese type 2 diabetic (T2D), obese nondiabetic (OND), and lean nondiabetic (LND) subjects. Insulin action/resistance was determined by a 3-hour hyperinsulinemic, euglycemic (5.0 to 5.5 mmol/L) clamp. Percutaneous biopsy of the vastus lateralis muscle was performed before and after the clamp. RXRalpha mRNA was measured using a quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay, while protein was determined by Western blotting. All 3 isoforms of RXR, alpha, beta, and gamma, were present in skeletal muscle. Protein expression of RXR isoforms did not differ between groups; RXR alpha mRNA was also similar between groups. Neither RXR alpha mRNA, RXR -beta nor -gamma protein displayed significant relationships with any of the clinical or laboratory parameters measured, including insulin sensitivity. RXR alpha exhibited a negative correlation with free fatty acids levels (r, -.42, P <.05). There was also no relationship between RXR alpha and PPARgamma protein levels. RXR alpha mRNA was unaltered following insulin infusion. We conclude that RXR isoform (alpha, beta, gamma) expression is not tightly controlled by insulin, insulin resistance or type 2 diabetes. Instead, RXR isoforms are likely constitutive proteins or controlled by other factors.

    Title Circulating Amylin in Human Essential Hypertension: Heritability and Early Increase in Individuals at Genetic Risk.
    Date June 2001
    Journal Journal of Hypertension
    Excerpt

    BACKGROUND: Human essential hypertension is a complex trait with poorly understood genetic determination. Insulin resistance is frequently associated with this trait. OBJECTIVE: To determine whether a potentially pathogenic feature of the insulin-resistant state, circulating amylin (islet amyloid polypeptide, co-released with insulin from pancreatic islet beta-cells), is already increased in prehypertensive individuals (normotensive persons at genetic risk of hypertension because of family history), whether such individuals already differ in their amylin response to beta-cell stimulation, and whether plasma amylin concentration is heritable. Such features could establish increased circulating amylin as a hereditary 'intermediate phenotype' useful in genetic analyses of hypertension. METHODS: Plasma amylin and insulin were measured in 283 medication-free individuals stratified by blood pressure status (82 hypertensive and 201 normotensive), and genetic risk (family history) of hypertension. Differences in means were tested by ANOVA, variances by F test, and frequency distributions by maximum likelihood analysis. Co-release of amylin and insulin was provoked by intravenous infusion of mixed amino acids. The effect of antihypertensive treatment was evaluated after monotherapy with either angiotensin converting enzyme inhibition or calcium-channel blockade in hypertension. RESULTS: Plasma amylin was increased in hypertension (P= 0.027), and body mass index was a strong predictor of increased circulating amylin (P = 0.0001). Plasma amylin and plasma renin activity were not correlated (P = 0.395), and effective antihypertensive monotherapy with either angiotensin converting enzyme inhibition or calcium-channel blockade did not affect either amylin (P = 0.87-0.97) or insulin (P= 0.55-0.59). Among normotensive individuals, those at genetic risk of hypertension (with positive family history) already had increased concentrations of amylin (P< 0.001), despite exhibiting no difference in blood pressure or body mass index compared with the family-history-negative group; however, among normotensive individuals, both family history (P = 0.043) and body mass index (P= 0.0059) were significant predictors of increased concentrations of amylin. By maximum likelihood analysis, plasma amylin was distributed heterogeneously in the normotensive individuals, with two modes best explaining the distribution (chi2 = 77.4, P< 0.001), and family-history-positive individuals completely accounting for the upper mode (chi2 = 4.63, P = 0.031). Family-history-positive normotensive individuals showed greater plasma amylin concentrations both before and during beta-cell stimulation by amino acid infusion (P = 0.014). Black (n = 111) and white (n = 172) individuals did not differ in mean (P = 0.946) or variance (P = 0.172) of plasma amylin concentrations. CONCLUSIONS: These results suggest that plasma amylin concentration is in part determined by heredity. Both basal and stimulated plasma amylin excess may identify a subgroup of individuals bearing an inherited predisposition to hypertension. Measurement of amylin might identify a useful 'intermediate phenotype' in the genetic analysis of essential hypertension and its relationship to insulin resistance.

    Title Early Alteration in Glomerular Reserve in Humans at Genetic Risk of Essential Hypertension: Mechanisms and Consequences.
    Date May 2001
    Journal Hypertension
    Excerpt

    Essential hypertension has a familial predisposition, but the phenotype of elevated blood pressure has delayed penetrance. Because the kidney is a crucial determinant of blood pressure homeostasis, we studied early glomerular alterations in still-normotensive young subjects at genetic risk of hypertension. Thirty-nine normotensive adults (mean age 29 to 31 years), stratified by genetic risk (parental family history [FH]) of hypertension (26 with positive FH [FH+], 13 with negative FH [FH-]), underwent intravenous infusion of mixed amino acids. Before and during amino acid administration, we measured glomerular filtration rate (GFR), putative second messengers of amino acids (nitric oxide [NO.] metabolites and cGMP), serum insulin and amino acid concentrations, and the FE(Li)+ as an index of renal proximal tubular reabsorption. The FH+ group had a blunted GFR rise in response to amino acids (2.43+/-8.16% versus 31.0+/-13.4% rise, P:=0.0126). The amino acid-induced change in GFR correlated (r=0.786, P:<0.01) with the change in urinary NO. metabolite excretion; a diminished rise in urinary NO. metabolite excretion in the FH+ group (P:=0.0105) suggested a biochemical mechanism for the different GFR responses between FH groups: a relative inability to convert arginine to NO. The FH+ group had a far lower initial cGMP excretion at baseline (261+/-21.1 versus 579+/-84.9 nmol. h(-1)/1.73 m(2), P:=0.001), although cGMP did not change during the amino acid infusion (P:=0.703). FH status, baseline GFR, and baseline serum insulin jointly predicted GFR response to amino acids (P:=0.0013), accounting for approximately 45% of the variance in GFR response. Decline in FE(Li)+, an inverse index of proximal tubular reabsorption, paralleled increase in GFR (r=-0.506, P:=0.01), suggesting differences in proximal tubular reabsorption during amino acids between the FH groups. GFR response to amino acid infusion was blunted in the FH+ group despite significantly higher serum concentrations of 6 amino acids (arginine, isoleucine, leucine, methionine, phenylalanine, and valine) in the FH+ group, suggesting a novel form of insulin resistance (to the amino acid-translocating action of insulin) in FH+ subjects. We conclude that blunted glomerular filtration reserve in response to amino acids is an early-penetrance phenotype seen even in still-normotensive subjects at genetic risk of hypertension and is linked to impaired formation of NO. in the kidney. Corresponding changes in GFR and fractional excretion of Li(+) suggest that altered proximal tubular reabsorption after amino acids is an early pathophysiologic mechanism. Resistance to the amino acid-translocating actions of insulin may play a role in the biological response to amino acids in this setting. This glomerular reserve phenotype may be useful in genetic studies of renal traits preceding or predisposing to hypertension.

    Title New Oral Therapies for Type 2 Diabetes Mellitus: The Glitazones or Insulin Sensitizers.
    Date April 2001
    Journal Annual Review of Medicine
    Excerpt

    Type 2 diabetes mellitus is a growing problem not only in the United States but also across the world. There is now strong evidence that intensive control of blood glucose can significantly reduce and retard the microvascular complications of retinopathy, nephropathy, and neuropathy. Ultimately however, up to 80% of type 2 diabetics die from macrovascular cardiovascular disease. This increased incidence of atherosclerotic disease is intricately associated with insulin resistance, which is a major pathophysiologic abnormality in type 2 diabetes. There is strong evidence that insulin resistance is involved in the development of not only hyperglycemia, but also dyslipidemia, hypertension, hypercoagulation, vasculopathy, and ultimately atherosclerotic cardiovascular disease. This cluster of metabolic abnormalities has been termed the insulin resistance or cardiovascular dysmetabolic syndrome. The thiazolidinediones (rosiglitazone and pioglitazone), a new class of oral antidiabetic agents, are "insulin sensitizers" and exert direct effects on the mechanisms of insulin resistance. These effects not only improve insulin sensitivity and glycemic control with reduced insulin requirements, but also have potentially favorable effects on other components of the cardiovascular dysmetabolic syndrome. Long-term studies are needed to determine whether the insulin-sensitizing effects of the glitazones can prevent or delay premature atherosclerotic cardiovascular disease, morbidity, and death.

    Title Induction of Insulin Resistance in Human Skeletal Muscle Cells by Downregulation of Glycogen Synthase Protein Expression.
    Date August 2000
    Journal Metabolism: Clinical and Experimental
    Excerpt

    Glycogen synthase (GS) is the rate-limiting enzyme controlling nonoxidative glucose disposal in skeletal muscle. A reduction in GS activity and an impaired insulin responsiveness are characteristic features of skeletal muscle in type 2 diabetes. These properties also exist in human skeletal muscle cell cultures from type 2 diabetic subjects. To determine the effect of an isolated reduction in GS on skeletal muscle insulin action, cultures from nondiabetic subjects were treated with antisense oligonucleotides (ODNs) to GS to interfere with expression of the gene. Treatment with antisense ODNs reduced GS protein expression by 70% compared with control (scrambled) ODNs (P < .01). GS activity measured at 0.01 mmol/L glucose-6-phosphate (G-6-P) was reduced by antisense ODN treatment. The insulin responsiveness of GS was impaired. Insulin also failed to stimulate glucose incorporation into glycogen after antisense ODN treatment. The cellular glycogen content was lower in antisense ODN-treated cells compared with control ODN. The insulin responsiveness of glucose uptake was abolished by antisense ODN treatment. Thus, reductions in GS expression in human skeletal muscle cells lead to impairments in insulin responsiveness and may play an important role in insulin-resistant states.

    Title Protein Kinase Ctheta Expression is Increased Upon Differentiation of Human Skeletal Muscle Cells: Dysregulation in Type 2 Diabetic Patients and a Possible Role for Protein Kinase Ctheta in Insulin-stimulated Glycogen Synthase Activity.
    Date August 2000
    Journal Endocrinology
    Excerpt

    Protein kinase C (PKCtheta) is a key enzyme in regulating a variety of cellular functions, including growth and differentiation. PKCtheta is the most abundant PKC isoform expressed in skeletal muscle; however, its role in differentiation and metabolism is not clear. We examined the effect of muscle cell differentiation on PKCtheta expression in human skeletal muscle cells from normal and type 2 diabetic subjects. Low levels of PKCtheta messenger RNA (mRNA) and protein were detected in human myoblasts from both types of subjects. Upon differentiation into myotubes, PKCtheta mRNA and protein were increased 12-fold in myotubes from normal subjects. In human skeletal muscle cells obtained from type 2 diabetic subjects, increases in PKCtheta mRNA and protein were not observed upon differentiation into myotubes although expression of other markers of differentiation and fusion increased. Cells from type 2 diabetic subjects also exhibited decreased insulin-stimulated glycogen synthase activity. To determine whether the up-regulation of PKCtheta was important for the metabolic actions of insulin, PKCtheta was overexpressed in L6 rat skeletal muscle cells. Increased expression of PKCtheta occurred with differentiation of skeletal muscle myoblasts to myotubes. Glycogen synthase activity was further increased in L6 myotubes stably transfected with the complementary DNA for PKCtheta. The decreased expression of PKCtheta found in cells from type 2 diabetic subjects may be linked to insulin resistance and decreased glycogen synthase activity.

    Title Potential Role of Glycogen Synthase Kinase-3 in Skeletal Muscle Insulin Resistance of Type 2 Diabetes.
    Date July 2000
    Journal Diabetes
    Excerpt

    Glycogen synthase (GS) activity is reduced in skeletal muscle of type 2 diabetes, despite normal protein expression, consistent with altered GS regulation. Glycogen synthase kinase-3 (GSK-3) is involved in regulation (phosphorylation and deactivation) of GS. To access the potential role of GSK-3 in insulin resistance and reduced GS activity in type 2 diabetes, the expression and activity of GSK-3 were studied in biopsies of vastus lateralis from type 2 and nondiabetic subjects before and after 3-h hyperinsulinemic (300 mU x m(-2) x min(-1))-euglycemic clamps. The specific activity of GSK-3alpha did not differ between nondiabetic and diabetic muscle and was decreased similarly after 3-h insulin infusion. However, protein levels of both alpha and beta isoforms of GSK-3 were elevated (approximately 30%) in diabetic muscle compared with lean (P < 0.01) and weight-matched obese nondiabetic subjects (P < 0.05) and were unchanged by insulin infusion. Thus, both basal and insulin-stimulated total GSK-3 activities were elevated by approximately twofold in diabetic muscle. GSK-3 expression was related to in vivo insulin action, as GSK-3 protein was negatively correlated with maximal insulin-stimulated glucose disposal rates. In summary, GSK-3 protein levels and total activities are 1) elevated in type 2 diabetic muscle independent of obesity and 2) inversely correlated with both GS activity and maximally insulin-stimulated glucose disposal. We conclude that increased GSK-3 expression in diabetic muscle may contribute to the impaired GS activity and skeletal muscle insulin resistance present in type 2 diabetes.

    Title Distribution of Peroxisome Proliferator-activated Receptors (ppars) in Human Skeletal Muscle and Adipose Tissue: Relation to Insulin Action.
    Date June 2000
    Journal Diabetologia
    Excerpt

    AIMS/HYPOTHESIS: To evaluate the tissue distribution and possible role of the peroxisome proliferator-activated receptors (PPARs) in insulin action in fat and muscle biopsy specimens from lean, obese and subjects with Type II (non-insulin-dependent) diabetes mellitus. METHODS: We measured PPAR alpha, PPAR beta (delta) and PPAR gamma protein expression by western blot analysis. The PPAR gamma protein was also measured in muscle before and after 3-h hyperinsulinaemic (300 mU.m-2.min-1) euglycaemic clamps. RESULTS: The PPAR alpha protein was expressed preferentially in muscle relative to fat (more than sevenfold). The PPAR beta protein was similar in fat and muscle. The amount of PPAR gamma protein found in muscle was, on average, two-thirds of that present in fat. There was no statistically significant difference between non-diabetic and diabetic subjects in baseline (preclamp) muscle PPAR (alpha, beta or gamma) protein expression. Subgroup analysis showed, however, significantly higher PPAR gamma protein in the most insulin resistant diabetic subjects with glucose disposal rates of 3-6 mg.kg-1.min-1 compared with their age and weight matched counterparts with glucose disposal rates of 6-9 (147 +/- 23 vs 88 +/- 10 AU/microgram protein, p < or = 0.01 in diabetic and vs 94 +/- 15, p < or = 0.04 in non-diabetic subjects). Muscle PPAR gamma protein and glucose disposal rates were inversely correlated in diabetic subjects (r = -0.47, p < or = 0.05). CONCLUSION/INTERPRETATION: All PPARs (alpha, beta or gamma) are present in skeletal muscle and adipose tissue with different relative distributions. The PPAR gamma protein is abundant in skeletal muscle as well as adipose tissue. The altered expression of skeletal muscle PPAR gamma is consistent with a role for this nuclear protein in the impaired insulin action of Type II diabetes.

    Title Duck Immune Responses to Riemerella Anatipestifer Vaccines.
    Date May 2000
    Journal Developmental and Comparative Immunology
    Excerpt

    Riemerella anatipestifer (Ra) infection is probably the most economically important infectious disease of farm ducks worldwide but the immune responses to natural infection and vaccines are poorly understood. We have used the lymphocyte transformation test (LTT) to study the expression of cell-mediated immunity (CMI), and the enzyme-linked immunosorbent assay to monitor antibody (Ab) production following administration of formalin-inactivated and live attenuated serotype 2 (= G) Ra vaccines. Lymphocytes (8x10(5) in 200 microl of RPMI + 10% duck serum, in 96 well trays) were stimulated with Ra antigen, prepared by freeze-thaw and sonication; optimum responses were obtained with antigen at 6.25 microg/ml. Cells were cultured for 3 days at 41.6 degrees C/5% CO(2), prior to assessing 3H-thymidine uptake. Ra bacterin, incorporating aluminium hydroxide as adjuvant, stimulated strong but transient (about 4 weeks) LTT response; there was some cross-reaction of the LTT to proteins derived from other serotypes of Ra. Revaccination stimulated slightly stronger responses with the same time course. The Ab response to each vaccination was longer-lived than the LTT response. Vaccination with a live, attenuated strain of Ra stimulated weaker but longer lasting LTT responses, but similar Ab responses compared to the bacterin. It is apparent, therefore, that the transient protection reported using Ra bacterins is due to the fact that the CMI response to these vaccines is transient; and that it is possible for ducks to have detectable levels of serum Ab at times when CMI is not detectable by LTT. These observations are important in terms of our understanding of immunopathogenesis, immunoprophylaxis, and immunodiagnosis in Ra.

    Title Insulin Aspart (b28 Asp-insulin): a Fast-acting Analog of Human Insulin: Absorption Kinetics and Action Profile Compared with Regular Human Insulin in Healthy Nondiabetic Subjects.
    Date November 1999
    Journal Diabetes Care
    Excerpt

    OBJECTIVE: To study the pharmacokinetic and pharmacodynamic profile of insulin aspart (a new fast-acting human insulin analog) after subcutaneous administration in the deltoid, abdominal, and thigh sites and to compare this profile with regular human insulin (Novolin; Novo Nordisk A/S, Copenhagen). RESEARCH DESIGN AND METHODS: A total of 20 healthy subjects were studied in a single-center six-period double-blind randomized crossover trial with 6 study days and a washout period of 1 week between each single daily dose of the trial drug. Subjects were randomized to receive a single dose of 0.2 U/kg of insulin aspart or regular insulin on each of the 6 study days in three different sites (the deltoid, the abdomen, and the thigh) during a 10-h euglycemic clamp (two drugs and three injection sites). Pharmacokinetic and pharmacodynamic measurements were derived from blood sample measurements of glucose, insulin, and C-peptide during these clamps. RESULTS: The pharmacodynamic data from the euglycemic clamp study showed that, regardless of injection site, the maximal glucose infusion rate (GIR Cmax) was greater and occurred at an earlier time (GIR Tmax) after administration of insulin aspart than regular insulin (GIR Cmax: abdomen 813 vs. 708, deltoid 861 vs. 736, and thigh 857 vs. 720 g/min, P < 0.05 for all; GIR Tmax: abdomen 94 vs. 173, deltoid 111 vs. 192, and thigh 145 vs. 193 g/min, P < 0.05 for all). Pharmacokinetic parameters were also consistent with faster absorption and higher peak insulin concentrations after insulin aspart administration. From all sites, the peak insulin concentration (Cmax) was higher and occurred earlier (Tmax) after administration of insulin aspart than of regular insulin (Cmax: abdomen 501 vs. 260, deltoid 506 vs. 252, thigh 422 vs. 220 pmol/l, P < 0.001 for all sites; Tmax: abdomen 52 vs. 109, deltoid 54 vs. 98, and thigh 60 vs. 107 min, P < 0.01 for all sites). The absorption and glucose-lowering action of insulin aspart did not differ between sites (similar GIR Cmax, Tmax, and area under the curve parameters). However, the duration of the glucose-lowering effect was up to 34 min shorter (P < 0.01) for the abdomen injections than for the deltoid or thigh injections (lower time of 50% glucose disposal). In addition, the amount of glucose infused was significantly lower by 10-14% in the abdomen than in other sites. CONCLUSIONS: Subcutaneous administration of insulin aspart causes a more rapid and intense maximal effect compared with regular insulin during euglycemic clamp studies in nondiabetic subjects. Abdominal administration of insulin aspart has a shorter duration of glucose-lowering effect compared with administration in the deltoid or thigh.

    Title Normal Insulin-dependent Activation of Akt/protein Kinase B, with Diminished Activation of Phosphoinositide 3-kinase, in Muscle in Type 2 Diabetes.
    Date October 1999
    Journal The Journal of Clinical Investigation
    Excerpt

    To determine whether the serine/threonine kinase Akt (also known as protein kinase B) is activated in vivo by insulin administration in humans, and whether impaired activation of Akt could play a role in insulin resistance, we measured the activity and phosphorylation of Akt isoforms in skeletal muscle from 3 groups of subjects: lean, obese nondiabetic, and obese type 2 diabetic. Vastus lateralis biopsies were taken in the basal (overnight fast) and insulin-stimulated (euglycemic clamp) states. Insulin-stimulated glucose disposal was reduced 31% in obese subjects and 63% in diabetic subjects, compared with lean subjects. Glycogen synthase (GS) activity in the basal state was reduced 28% in obese subjects and 49% in diabetic subjects, compared with lean subjects. Insulin-stimulated GS activity was reduced 30% in diabetic subjects. Insulin treatment activated the insulin receptor substrate-1-associated (IRS-1-associated) phosphoinositide 3-kinase (PI 3-kinase) 6.1-fold in lean, 3.7-fold in obese, and 2.4-fold in diabetic subjects. Insulin also stimulated IRS-2-associated PI 3-kinase activity 2.2-fold in lean subjects, but only 1.4-fold in diabetic subjects. Basal activity of Akt1/Akt2 (Akt1/2) and Akt3 was similar in all groups. Insulin increased Akt1/2 activity 1.7- to 2. 0-fold, and tended to activate Akt3, in all groups. Insulin-stimulated phosphorylation of Akt1/2 was normal in obese and diabetic subjects. In lean subjects only, insulin-stimulated Akt1/2 activity correlated with glucose disposal rate. Thus, insulin activation of Akt isoforms is normal in muscle of obese nondiabetic and obese diabetic subjects, despite decreases of approximately 50% and 39% in IRS-1- and IRS-2-associated PI 3-kinase activity, respectively, in obese diabetic subjects. It is therefore unlikely that Akt plays a major role in the resistance to insulin action on glucose disposal or GS activation that is observed in muscle of obese type 2 diabetic subjects.

    Title Glucosamine Regulation of Glucose Metabolism in Cultured Human Skeletal Muscle Cells: Divergent Effects on Glucose Transport/phosphorylation and Glycogen Synthase in Non-diabetic and Type 2 Diabetic Subjects.
    Date September 1999
    Journal Endocrinology
    Excerpt

    Chronic exposure (48 h) to glucosamine resulted in a dose-dependent reduction of basal and insulin-stimulated glucose uptake activities in human skeletal muscle cell cultures from nondiabetic and type 2 diabetic subjects. Insulin responsiveness of uptake was also reduced. There was no change in total membrane expression of either GLUT1, GLUT3, or GLUT4 proteins. While glucosamine treatment had no significant effects on hexokinase activity measured in cell extracts, glucose phosphorylation in intact cells was impaired after treatment. Under conditions where glucose transport and phosphorylation were down regulated, the fractional velocity (FV) of glycogen synthase was increased by glucosamine treatment. Neither the total activity nor protein expression of glycogen synthase were influenced by glucosamine treatment. The stimulation of glycogen synthase by glucosamine was not due totally to soluble mediators. Reflective of the effects on transport/phosphorylation, total glycogen content and net glycogen synthesis were reduced after glucosamine treatment. These effects were similar in nondiabetic and type 2 cells. In summary: 1) Chronic treatment with glucosamine reduces glucose transport/phosphorylation and storage into glycogen in skeletal muscle cells in culture and impairs insulin responsiveness as well. 2) Down-regulation of glucose transport/phosphorylation occurs at a posttranslational level of GLUTs. 3) Glycogen synthase activity increases with glucosamine treatment. 4) Nondiabetic and type 2 muscle cells display equal sensitivity and responsiveness to glucosamine. Increased exposure of skeletal muscle to glucosamine, a substrate/precursor of the hexosamine pathway, alters intracellular glucose metabolism at multiple sites and can contribute to insulin resistance in this tissue.

    Title Measles, Hmong, and Metaphor: Culture Change and Illness Management Under Conditions of Immigration.
    Date June 1999
    Journal Medical Anthropology Quarterly
    Excerpt

    When 19 Hmong families and three healers in St. Paul, Minnesota, were interviewed regarding their understanding of measles and the ways in which they cared for children with the disease, their responses spanned the range between Hmong animistic cosmology and Western theories of disease. The metaphors of growth that were used to describe the disease link language, cosmology, causation, body processes, and illness management practices. This study discusses the themes of cyclical time, disease-causing spirits, the natural/supernatural dichotomy, and agricultural metaphors as applied to disease, as well as the growing adaptation to, use of, and interpretation of Western medicine by these immigrants.

    Title Inhibition of Ldl Oxidation in Vitro but Not Ex Vivo by Troglitazone.
    Date April 1999
    Journal Diabetes
    Excerpt

    Diabetic subjects are at increased risk for developing coronary artery disease, in part because of increased oxidation of LDL, which promotes atherogenesis. Troglitazone, a new antidiabetic drug of the thiazolidinedione class, acts as an insulin sensitizer and improves hyperglycemia. Structurally, it contains a tocopherol moiety similar to vitamin E and has been shown to have antioxidant properties in vitro. Therefore, we evaluated whether troglitazone inhibited LDL oxidation both in vitro and in type 2 diabetic subjects ex vivo. Troglitazone inhibited oxidation of LDL induced by Cu2+ or 2'2'-azobis-2-amidinopropane hydrochloride (AAPH) with 50% inhibition at 1 micromol/l and 100% inhibition at 5-10 micromol/l troglitazone. The inhibition of LDL oxidation by troglitazone also was time dependent. In addition, troglitazone inhibited oxidation of 125I-labeled LDL and its subsequent uptake and degradation by macrophages. To determine whether troglitazone was incorporated into LDL particles or acted in the aqueous milieu, troglitazone was incubated overnight at 37 degrees C with LDL or plasma before LDL re-isolation. After re-isolation, LDL that was incubated with troglitazone was no longer protected from oxidation, compared with probucol-treated LDL, which remained protected. Further, [14C]troglitazone did not get incorporated into LDL. This suggests that troglitazone exerts its antioxidant effect in the aqueous milieu of LDL. Consistent with this was the observation that the lag phases of copper-induced conjugated diene formation, a measure of the susceptibility in vivo, was similar for subjects taking troglitazone (76 +/- 5 min, n = 9) to subjects not taking the drug (77 +/- 3 min, n = 11; NS). Thus, troglitazone may be of value as an aqueous-phase antioxidant in addition to its effect on glucose homeostasis.

    Title Effects of Tumor Necrosis Factor-alpha on Glucose Metabolism in Cultured Human Muscle Cells from Nondiabetic and Type 2 Diabetic Subjects.
    Date December 1998
    Journal Endocrinology
    Excerpt

    The effects of tumor necrosis factor-alpha (TNF alpha) on glucose uptake and glycogen synthase (GS) activity were studied in human skeletal muscle cell cultures from nondiabetic and type 2 diabetic subjects. In nondiabetic muscle cells, acute (90-min) exposure to TNF alpha (5 ng/ml) stimulated glucose uptake (73 +/- 14% increase) to a greater extent than insulin (37 +/- 4%; P < 0.02). The acute uptake response to TNF alpha in diabetic cells (51 +/- 6% increase) was also greater than that to insulin (31 +/- 3%; P < 0.05). Prolonged (24-h) exposure of nondiabetic muscle cells to TNF alpha resulted in a further stimulation of uptake (152 +/- 31%; P < 0.05), whereas the increase in cells from type 2 diabetics was not significant compared with that in cells receiving acute treatment. After TNF alpha treatment, the level of glucose transporter-1 protein was elevated in nondiabetic (4.6-fold increase) and type 2 (1.7-fold) cells. Acute TNF alpha treatment had no effect on the fractional velocity of GS in either nondiabetic or type 2 cells. Prolonged exposure reduced the GS fractional velocity in both nondiabetic and diabetic cells. In summary, both acute and prolonged treatment with TNF alpha up-regulate glucose uptake activity in cultured human muscle cells, but reduce GS activity. Increased skeletal muscle glucose uptake in conditions of TNF alpha excess may serve as a compensatory mechanism in the insulin resistance of type 2 diabetes.

    Title The Veterans Affairs Implantable Insulin Pump Study: Effect on Cardiovascular Risk Factors.
    Date December 1998
    Journal Diabetes Care
    Excerpt

    OBJECTIVE: To determine whether implantable insulin pump (IIP) and multiple-dose insulin (MDI) therapy have different effects on cardiovascular risk factors in insulin-requiring patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized clinical trial was conducted at seven Veterans Affairs medical centers in 121 male patients with type 2 diabetes between the ages of 40 and 69 years receiving at least one injection of insulin per day and with HbA1c, levels of > or =8% at baseline. Weights, blood pressures, insulin use, and glucose monitoring data were obtained at each visit. Lipid levels were obtained at 0, 4, 8, and 12 months, and free and total insulin levels were obtained at 0, 6, and 12 months. All medications being taken were recorded at each visit. RESULTS: No difference in absolute blood pressure, neither systolic nor diastolic, was seen between patients receiving MDI or IIP therapy, but significantly more MDI patients required anti-hypertensive medications. When blood pressure was modeled against weight and time, IIP therapy was significantly better than MDI therapy for systolic blood pressure in patients with BMI <33 and for diastolic blood pressure in patients with BMI >34 kg/m2. Total cholesterol levels decreased in the overall sample, but IIP patients exhibited significantly higher levels than MDI patients. Triglyceride levels increased over time for both groups, with IIP patients having significantly higher levels than patients in the MDI group. BMI was a significant predictor of, and inversely proportional to, HDL cholesterol level. No difference in lipid-lowering drug therapy was seen between the two groups. Free insulin and insulin antibodies tended to decrease in the IIP group as compared with the MDI group. C-peptide levels decreased in both groups. CONCLUSIONS: IIP therapy in insulin-requiring patients with type 2 diabetes has advantages over MDI therapy in decreasing the requirement for antihypertensive therapy and for decreasing total and free insulin and insulin antibodies. Both therapies reduce total cholesterol and C-peptide levels.

    Title Troglitazone Effects on Gene Expression in Human Skeletal Muscle of Type Ii Diabetes Involve Up-regulation of Peroxisome Proliferator-activated Receptor-gamma.
    Date September 1998
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    Troglitazone, besides improving insulin action in insulin-resistant subjects, is also a specific ligand for the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma). To determine whether troglitazone might enhance insulin action by stimulation of PPARgamma gene expression in muscle, total PPARgamma messenger RNA (mRNA), and protein were determined in skeletal muscle cultures from nondiabetic control and type II diabetic subjects before and after treatment of cultures with troglitazone (4 days +/- troglitazone, 11.5 microM). Troglitazone treatment increased PPARgamma mRNA levels up to 3-fold in muscle cultures from type II diabetics (277 +/- 63 to 630 +/- 100 x 10(3) copies/microg total RNA, P = 0.003) and in nondiabetic control subjects (200 +/- 42 to 490 +/- 81, P = 0.003). PPARgamma protein levels in both diabetic (4.7 +/- 1.6 to 13.6 +/- 3.0 AU/10 microg protein, P < 0.02) and nondiabetic cells (7.4 +/- 1.0 to 12.7 +/- 1.8, P < 0.05) were also upregulated by troglitazone treatment. Increased PPARgamma was associated with stimulation of human adipocyte lipid binding protein (ALBP) and muscle fatty acid binding protein (mFABP) mRNA, without change in the mRNA for glycerol-3-phosphate dehydrogenase, PPARdelta, myogenin, uncoupling protein-2, or sarcomeric alpha-actin protein. In summary, we showed that troglitazone markedly induces PPARgamma, ALBP, and mFABP mRNA abundance in muscle cultures from both nondiabetic and type II diabetic subjects. Increased expression of PPARgamma protein and other genes involved in glucose and lipid metabolism in skeletal muscle may account, in part, for the insulin sensitizing effects of troglitazone in type II diabetes.

    Title Type 2 Diabetes Care: the Role of Insulin-sensitizing Agents and Practical Implications for Cardiovascular Disease Prevention.
    Date August 1998
    Journal The American Journal of Medicine
    Excerpt

    Millions of Americans are at risk for cardiovascular morbidity and mortality related to disorders of glucose intolerance--particularly type 2 diabetes and prediabetic conditions, including the insulin resistance, or "cardiovascular dysmetabolic," syndrome. The latter is apparently more intricately associated with macrovascular disease--myocardial infarction, stroke, and peripheral vascular disease. In some situations the risk of cardiovascular disease might be reduced by the prevention of diabetes and also by prevention or treatment of the cardiovascular dysmetabolic syndrome. Studies have shown that intensive glycemic control can delay the development of microvascular complications in type 1, and possibly type 2, diabetes. Several longitudinal observational studies have demonstrated a relationship between glycemic control and the development of cardiovascular disease. Prospective clinical intervention trials to address this issue are underway. Insulin may have a role in atherogenesis, both directly and by promoting development of such risk factors as hypertension and dyslipidemia. Genetic factors and mechanisms promoting or discouraging development of glucose intolerance are also under investigation. Lifestyle changes--dietary and exercise modification, weight loss, and smoking cessation--have been shown to have a positive effect on cardiovascular disease risk. Clinical trials suggest that oral antidiabetic agents--particularly the new noninsulin secretagogues (including troglitazone and metformin, which act on the liver and on skeletal muscle)--may be useful in delaying or preventing development of type 2 diabetes and the cardiovascular dysmetabolic syndrome, as well as in their treatment, when present. Both agents, acting primarily by different mechanisms of action, have also demonstrated potential beneficial effects on serum lipid profiles and other cardiovascular risk factors and may be useful in patients with cardiovascular dysmetabolic syndrome who do not yet meet the criteria for diabetes.

    Title Plasma Homocysteine Concentrations Are Regulated by Acute Hyperinsulinemia in Nondiabetic but Not Type 2 Diabetic Subjects.
    Date July 1998
    Journal Metabolism: Clinical and Experimental
    Excerpt

    An association between hyperhomocysteinemia and premature atherosclerosis in patients with non-insulin-dependent diabetes mellitus (NIDDM) has recently been described. Little is known about the role of insulin in homocysteine [H(e)] metabolism. We measured plasma H(e) concentrations in the fasting state and during a hyperinsulinemic-euglycemic clamp in normal subjects and patients with NIDDM. Plasma H(e) decreased significantly from 7.2 +/- 2.6 to 6.0 +/- 2.7 mmol/L (P < .01) in normal subjects, but did not change in patients with NIDDM (6.0 +/- 2.7 to 5.9 +/- 2.5 mmol/L, respectively). These data suggest that plasma H(e) concentrations are regulated by acute hyperinsulinemia in normal subjects, but not in insulin-resistant NIDDM subjects. These abnormalities may have implications for the pathogenesis of premature vascular disease associated with NIDDM.

    Title Troglitazone Regulation of Glucose Metabolism in Human Skeletal Muscle Cultures from Obese Type Ii Diabetic Subjects.
    Date June 1998
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    To determine the effects of troglitazone on abnormal skeletal muscle glucose metabolism, muscle cultures from type II diabetic patients were grown for 4-6 weeks and then fused for 4 days either without or with troglitazone (1-5 micrograms/mL; chronic studies) or had troglitazone added for 90 min (1-5 micrograms/mL) at completion of fusion (acute studies). Acute troglitazone treatment stimulated glucose uptake, but not glycogen synthase (GS) activity 2-fold (P < 0.05) in a dose-dependent fashion and to the same extent as the addition of maximal (33 nmol/L) insulin. Maximal chronic troglitazone (5 micrograms/mL for 4 days) increased both glucose uptake (from 9.0 +/- 1.5 to 40.9 +/- 8.1 pmol/mg protein.min; P < 0.05) and GS fractional velocity (from 5.4 +/- 0.7% to 20.6 +/- 6.3%; P < 0.05) by approximately 4-fold. At each concentration of chronic troglitazone, glucose uptake rates were similar in the absence and presence of maximal (33 nmol/L) insulin concentrations. In contrast, insulin-stimulated GS activity was greater (P < 0.05) when maximal chronic troglitazone and acute insulin were combined than when chronic troglitazone alone was used. After 4 days of troglitazone, GLUT1 messenger ribonucleic acid and protein increased about 2-fold (P < 0.05) without a change in GLUT4 or GS messenger ribonucleic acid and protein. We conclude that troglitazone has both acute and chronic effects to improve skeletal muscle glucose metabolism of obese type II diabetic subjects. These effects involve direct insulin mimetic stimulatory actions as well as indirect insulin-sensitizing properties.

    Title Elevated Cyclins and Cyclin-dependent Kinase Activity in the Rhabdomyosarcoma Cell Line Rd.
    Date June 1998
    Journal Cancer Research
    Excerpt

    An important early event in the differentiation of skeletal muscle cells is exit from the cell cycle, after which full expression of the muscle phenotype occurs. Rhabdomyosarcoma (RMS), a tumor of skeletal muscle origin, expresses a number of muscle-specific proteins, including MyoD; however, these cells fail to arrest or differentiate when cultured in differentiation medium (DM). To determine the basis for the failure of RMS cells to differentiate or arrest, we studied the molecular response of the embryonal RMS cell line, RD, to culture in DM. Under these conditions, the retinoblastoma protein (RB) was primarily in the hyperphosphorylated state. This is in contrast to myoblasts cultured in DM, in which the hypophosphorylated form of RB is exclusively present. Measurements of the expression and activities of cyclin-dependent kinases (cdks) cdk2 and cdk4 indicated that RD cells maintained higher levels than do myoblasts, and the activity and abundance of these proteins did not significantly decrease upon culture in DM in RD cells, as they did in myoblasts. Similarly, elevated expression of cyclins D1, E, and A was observed in RD cells. Interestingly, cdk inhibitors are expressed in RD cells, with p16ink4 expression markedly elevated relative to myoblasts. Ectopic expression of p21cip1, p16ink4, or p27kip1 caused a growth arrest of RD cells but not detectable expression of a myogenic marker. Furthermore, a constitutively active RB protein could also inhibit the growth of RD cells without inducing myogenic differentiation. Taken together, these data suggest that the elevated levels of cdk2 and/or cdk4 observed in RD cells contribute to the inability of RD cells to growth arrest when cultured in DM but that these activities alone are not responsible for the failure of RD cells to differentiate.

    Title Lack of Effect of Leptin on Glucose Transport, Lipoprotein Lipase, and Insulin Action in Adipose and Muscle Cells.
    Date May 1998
    Journal Endocrinology
    Excerpt

    The effect of leptin on glucose transport, lipogenesis, and lipoprotein lipase activity was studied in cultured rat adipocytes and 3T3-L1 adipocytes. Leptin had no effect on basal and insulin stimulated glucose transport in isolated adipocytes from the rat and the genetically obese mouse. The incorporation of glucose into lipids was also unaffected. Lipoprotein lipase (LPL) activity remained unchanged in response to leptin in these cells, as well as in minced adipose tissue. Leptin also had no effect on both basal and insulin-stimulated glucose transport in cultured rat and human skeletal muscle cells. These studies showed that leptin had no effect on glucose transport, lipoprotein lipase activity, and insulin action in fat and muscle cells in vitro.

    Title Thiazolidinediones and Their Effects on Glucose Transporters.
    Date February 1998
    Journal European Journal of Endocrinology / European Federation of Endocrine Societies
    Title Thiazolidinediones.
    Date January 1998
    Journal Endocrinology and Metabolism Clinics of North America
    Excerpt

    The thiazolidinediones are a unique class of compounds that exert direct effects on the mechanisms of insulin resistance and result in improved insulin action and reduced hyperinsulinemia. Troglitazone is the first of these compounds to be approved for use in humans and has the potential not only to reduce glycemia and insulin requirements in type II diabetes but to improve other components of the insulin resistance syndrome including dyslipidemia, hypertension, and accelerated cardiovascular disease. Such compounds also hold promise for the prevention of type II diabetes and for the treatment of other insulin-resistant states including polycystic ovary disease. In addition to the novel mechanism of action through binding and activation of PPARs, troglitazone has other unique advantages, including once-a-day administration, a low incidence of minor side effects, no known drug interactions, hepatic metabolism and secretion, and potent antioxidant properties. Thiazolidinedione compounds such as troglitazone provide an important additional resource for the health care provider in the management of type II diabetes and other components of the insulin resistance syndrome.

    Title Risk and Resilience in the Cognitive Functioning of Children Born to Hiv-1-infected Mothers: a Preliminary Report.
    Date August 1997
    Journal Pediatric Aids and Hiv Infection
    Excerpt

    Although biologic and environmental risk factors show an age-dependent effect on children's cognitive development, outcome studies have yet to consider the role such factors play in the development of children born to HIV-1-infected women. This study explored the age-dependent differential impact of such risk factors on the cognitive functioning of children exposed in utero to HIV-1. Eighty-two children were administered a standardized measure of cognitive functioning and divided into two groups depending on their age when tested. Group 1 included children age 2 to 29 months (n = 46); Group 2 included children age 30 to 101 months (n = 36). Correlations between cognitive test scores and specific risk factors revealed an age-related double-dissociation. Serostatus and percent of CD4 cells correlated moderately with cognitive test scores in Group 1; however, these correlations were attenuated and nonsignificant in Group 2. Conversely, caregiver status and cognitive test scores were uncorrelated in Group 1, but were correlated in Group 2. These findings support a risk and resilience model of development. That is, in the context of biologic risk factors, aspects of the child's environment may either facilitate or hinder cognitive development.

    Title Non-insulin-dependent Diabetes Mellitus.
    Date July 1997
    Journal Current Therapy in Endocrinology and Metabolism
    Title Obesity.
    Date July 1997
    Journal Current Therapy in Endocrinology and Metabolism
    Title Ppar-gamma Gene Expression is Elevated in Skeletal Muscle of Obese and Type Ii Diabetic Subjects.
    Date July 1997
    Journal Diabetes
    Excerpt

    The peroxisome proliferator activated receptor PPAR-gamma has been identified as a nuclear receptor for thiazolidenediones, which are compounds with insulin-sensitizing properties in several tissues, including skeletal muscle. To determine whether this receptor is expressed and possibly involved in insulin action/resistance in skeletal muscle, PPAR-gamma mRNA abundance and its regulation by insulin were quantified in muscle tissue and cultures from lean and obese nondiabetic and type II diabetic subjects using competitive reverse transcription-polymerase chain reaction (RT-PCR). In muscle biopsy specimens, PPAR-gamma mRNA was elevated in obese nondiabetic and type II diabetic subjects (23.4 +/- 4.2 and 28.0 +/- 5.69 x 10(3) copies/microg total RNA, respectively; both P < 0.05) compared with lean nondiabetic control subjects (9.4 +/- 2.3 x 10(3) copies/microg total RNA). Significant positive correlations were present among skeletal muscle PPAR-gamma mRNA levels, BMI (r = 0.67, P < 0.01), and fasting insulin concentration (r = 0.76, P < 0.001). PPAR-gamma mRNA levels were also elevated in muscle cultures from type II diabetic subjects compared with lean nondiabetic control subjects (330.1 +/- 52.9 vs. 192.1 +/- 27.0 x 10(3) copies/microg total RNA, P < 0.05). Insulin stimulation of muscle tissue (by hyperinsulinemic-euglycemic clamp for 3-4 h) or muscle cultures (30 nmol/l for 120 min) stimulated PPAR-gamma mRNA expression up to fourfold (10.0 +/- 2.7 to 41.3 +/- 7.4 x 10(3) copies/microg total RNA, P < 0.05, and 174.9 +/- 56.9 to 268.2 +/- 78.6 x 10(3) copies/microg total RNA, P < 0.05, respectively). In summary, PPAR-gamma mRNA expression in human skeletal muscle is acutely regulated by insulin and is increased in both obese nondiabetic and type II diabetic subjects in direct relation to BMI and fasting insulinemia. We conclude that abnormalities of PPAR-gamma may be involved in skeletal muscle insulin resistance of obesity and type II diabetes.

    Title Regulation of Glycogen Synthase Activity in Cultured Skeletal Muscle Cells from Subjects with Type Ii Diabetes: Role of Chronic Hyperinsulinemia and Hyperglycemia.
    Date June 1997
    Journal Diabetes
    Excerpt

    Human skeletal muscle cultures (HSMCs) from type II diabetic subjects were used to determine whether metabolic abnormalities such as hyperglycemia or hyperinsulinemia contribute to the defective muscle glycogen synthase (GS) activity present in this disorder. Following approximately 6 weeks of growth, diabetic cultures were fused for 4 days in normal, hyperglycemia, or hyperinsulinemia medium. Fusion of diabetic HSMCs in hyperglycemia medium (20 mmol/l vs. 5.5 mmol/l) had no effect on GS fractional velocity (FV) or mRNA levels, but impaired acute insulin-stimulation of glycogen synthesis and GS activity at 0.1 mmol/l glucose-6-phosphate, and reduced GS protein content by approximately 15% (P < 0.05). Fusion of diabetic muscle cultures in hyperinsulinemia medium (30 micromol/l vs. 22 pmol/l) improved basal GS activity, increasing the reduced GS FV by approximately 50% (P < 0.05), and decreasing the elevated Km(0.1) (half-maximal substrate concentration) by approximately 47% (P < 0.05). Hyperinsulinemia also significantly increased (P < 0.05) the reduced GS mRNA and protein levels of diabetic muscle to levels similar to that in nondiabetic subjects. In contrast to the improvements in the basal state, hyperinsulinemia completely abolished acute insulin responsiveness of GS activity and glycogen synthesis in muscle of type II diabetic subjects. The combination of hyperinsulinemia and hyperglycemia produced effects on both basal and insulin-responsive GS FV and mRNA similar to hyperinsulinemia alone, but hyperinsulinemia prevented hyperglycemia's effect of lowering GS protein and glycogen synthesis. We concluded that, in diabetic muscle, hyperinsulinemia may serve to partially compensate for the impaired basal GS activity and for the adverse effects of hyperglycemia on GS protein content, activity, and glycogen formation by both pre- and posttranslational mechanisms. Despite these beneficial effects, hyperinsulinemia also induces severe impairment of insulin-stimulated GS activity and glycogen formation, which may contribute to acquired muscle insulin resistance of type II diabetes.

    Title Effects of Multiple Daily Insulin Injections and Intraperitoneal Insulin Therapy on Cholesteryl Ester Transfer and Lipoprotein Lipase Activities in Niddm.
    Date March 1997
    Journal Diabetes
    Excerpt

    Although the relationship between the actions of cholesteryl ester transfer protein (CETP) and atherosclerosis is complex, a strong body of evidence suggests that its activity (cholesteryl ester transfer [CET]) is proatherogenic. We have previously shown that CET is increased in IDDM patients receiving conventional subcutaneous insulin treatment and normalized when systemic insulin levels are lowered with intraperitoneal insulin delivery (IP). Since CET has been found by many observers to also be accelerated in NIDDM, we sought to determine whether the same salutary effect could be achieved in insulin-requiring NIDDM men before and 7 months after randomization to an intensive treatment regimen (Rx) of either IP (n = 9) or multiple daily insulin injections (MDI; n = 13). HbA1c improved to the same degree in both groups (MDI group: 9.4 +/- 1.1% pre-Rx vs. 7.2 +/- 0.7% post-Rx [P < 0.001]; IP group: 9.2 +/- 1.3% pre-Rx vs. 7.1 +/- 0.5% post-Rx [P < 0.001]). Compared with pre-Rx levels, plasma triglycerides were not significantly changed by either treatment (MDI group: 136 +/- 80 mg/dl pre-Rx vs. 139 +/- 87 mg/dl post-Rx; IP group: 157 +/- 63 mg/dl pre-Rx vs. 188 +/- 89 mg/dl post-Rx), though an upward trend followed IP. Before randomization, CET estimated with both mass and isotopic assays was greater in the NIDDM subjects than in nondiabetic control subjects (P < 0.001). With improved glycemic control, CE mass transfer declined in both groups, but only reached normal levels in the IP group (MDI group at 2 h: 49.0 +/- 13.7 [mean +/- SD] pg pre-Rx vs. 29.5 +/- 15.3 microg post-Rx [-39.7%, P < 0.01]; IP group at 2 h: 40.8 +/- 23.3 microg pre-Rx vs. 10.9 +/- 6.5 microg post-Rx [-73.2%, P < 0.05]) and remained abnormally increased (P < 0.005) in the subjects receiving MDI. Total lipolytic activity after intensive treatment was unchanged from pretreatment levels, which were similar to those of the reference group. Although directional changes in lipoprotein lipase (LpL) and hepatic triglyceride lipase (HTGL) similar to those found in IDDM after MDI and IP were observed, they were not statistically significant. Thus, while improved glycemic control alone achieved by either MDI or IP reduced the pathological increase in CET in these insulin-treated NIDDM men, normalization was only achieved in those treated with IP. Despite near-normal HbA1c levels, CET remained abnormally increased in NIDDM patients treated rigorously with conventional subcutaneous insulin delivery.

    Title Acute Effects of Intraperitoneal Versus Subcutaneous Insulin Delivery on Glucose Homeostasis in Patients with Niddm. Veterans Affairs Implantable Insulin Pump Study Group.
    Date February 1997
    Journal Diabetes Care
    Excerpt

    OBJECTIVE: The objective of this study is to compare the effect of intraperitoneal versus subcutaneous insulin injection on hepatic glucose production (HGP) and systemic glucose utilization (Rd) in patients with NIDDM. RESEARCH DESIGN AND METHODS: Eight male volunteers with NIDDM, each of whom had a programmable-rate, implantable insulin pump, were given an injection of insulin (0.15 units/kg body wt) by intraperitoneal or subcutaneous injection on separate days in randomized order. Plasma glucose was kept constant for 5 h using the glucose clamp technique, and HGP and Rd were measured using isotope dilution. RESULTS: Intraperitoneal insulin injection resulted in higher and earlier peak systemic insulin concentrations (1,469 +/- 245 vs. 454 +/- 48 pmol/l, P < 0.01). Glucose Rd doubled within 1 h after intraperitoneal injection and was greater than that attained with subcutaneous injection (3.91 +/- 0.27 vs. 2.60 +/- 0.19 mg.kg-1.min-1, P < 0.01). Intraperitoneal and subcutaneous injections suppressed HGP and plasma free fatty acid to a similar extent during the first 3 h, effects tht persisted through 5 h after subcutaneous insulin injection but waned 3-4 h after intraperitoneal injection. CONCLUSIONS: In patients with NIDDM, intraperitoneal insulin injection achieves more rapid and greater peak values for stimulation of glucose Rd than subcutaneous insulin injection. With regard to HGP and lipolysis, intraperitoneal and subcutaneous injections achieve similar initial suppression but this is maintained for a more limited duration with intraperitoneal as compared with subcutaneous injection. These differences in insulin action seem directly related to the rapidity of insulin absorption with intraperitoneal injection.

    Title Strategies for Preventing Type Ii Diabetes. What Can Be Done to Stem the Epidemic?
    Date February 1997
    Journal Postgraduate Medicine
    Excerpt

    Non-insulin-dependent (type II) diabetes is a major target for prevention because of its staggering emotional and financial burdens on society. The theory behind preventive efforts is that individuals at high risk often show signs of impaired glucose tolerance before diabetes fully develops. Once identified, these patients may respond to several pharmacologic and nonpharmacologic interventions that lower blood glucose levels and improve cardiovascular fitness with few adverse effects. However, the long-term efficacy of these approaches is uncertain. Information from the National Institutes of Health Diabetes Prevention Program should help clarify the impact of preventive measures and their cost-effectiveness.

    Title Effects of Troglitazone on Insulin Sensitivity.
    Date February 1997
    Journal Diabetic Medicine : a Journal of the British Diabetic Association
    Excerpt

    Studies to date confirm that troglitazone has therapeutic benefits to NIDDM and can normalize IGT in those individuals at increased risk of developing NIDDM. Hyperinsulinaemia is reduced by such treatment in association with reduced insulin resistance and there are favourable effects on blood pressure with troglitazone therapy as well. Since insulin resistance and hyperinsulinaemia are usually present in obesity and impaired glucose tolerance (IGT), troglitazone may be useful in preventing the development of NIDDM in these susceptible populations.

    Title Mechanisms of Tumor-induced Hypoglycemia with Intraabdominal Hemangiopericytoma.
    Date December 1996
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    The association of hypoglycemia with nonislet cell tumors is well recognized and in nearly all instances has been related to the production of hormones with insulin-like activity. To determine the mechanism of such tumor-induced hypoglycemia and the response to pharmacological intervention, we studied a 54-yr-old man with refractory hypoglycemia and a large intraabdominal hemangiopericytoma. During a supervised fast, plasma glucose decreased to 2.2 mmol/L. Circulating insulin (< 7 pmol/L), C peptide (< 0.04 nmol/L), and GH levels (< 0.6 microgram/L) were all undetectable, insulin-like growth factor I (IGF-I; 5 nmol/L) was low, IGF-II was in the normal range (87 nmol/L), and free IGF-II and big IGF-II (E1-21 fragment) were elevated at 18 and 142 nmol/L, respectively. On another day, after maintaining euglycemia overnight with a 20% dextrose infusion, a euglycemic (5.0-5.5 mmol/L) glucose clamp study using [3-3H]glucose tracer infusion combined with arteriovenous leg catheterization was performed in the postabsorptive basal state and during 3 h of crystalline somatostatin infusion (0.08-0.24 pmol/kg min). In the postabsorptive state at euglycemia, free IGF-II and big IGF-II remained elevated at 16 and 162 nmol/L, respectively. Whole body glucose disposal was elevated at 21.1 mumol/kg.min, whereas the rate of glucose infusion was 12.1 mumol/kg.min, and depatic glucose output was 7.8 mumol/kg.min. The leg arterio-venous plasma glucose difference was increased at 0.6 mmol/L, as was leg glucose uptake at 203.9 mumol/min. After 3 h of somatostatin infusion, both free and big IGF-II decreased by 35-40% to 10 and 102 nmol/L, respectively. Whole body glucose disposal also decreased to near normal (12.8 mumol/kg.min), whereas leg arterio-venous plasma glucose difference and leg glucose uptake became negligible. The plasma glucose level remained at 5.0-5.5 mmol/L despite a marked fall in hepatic glucose output to 2.9 mumol/kg.min and a decrease in glucose infusion rate to 8.7 mumol/kg.min. During somatostatin treatment, GH remained suppressed at less than 0.6 microgram/L, and glucagon decreased from 99 to 78 ng/L. In this patient with a hemangiopericytoma, hypoglycemia was associated with increased circulating insulin-like activity from elevated free and big IGF-II, which stimulated glucose uptake primarily into muscle tissue. A continuous infusion of crystalline somatostatin effectively reduced the elevated levels of IGF-II and glucose uptake, but was unable to adequately control hypoglycemia without the simultaneous infusion of exogenous glucose or glucagon.

    Title Abnormalities of Insulin Pulsatility and Glucose Oscillations During Meals in Obese Noninsulin-dependent Diabetic Patients: Effects of Weight Reduction.
    Date December 1996
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    Twenty-seven obese patients, including 8 with normal glucose tolerance, 10 with subclinical NIDDM, and 9 with overt noninsulin-dependent diabetes mellitus (NIDDM), were studied before and after prolonged weight loss to assess the effects of the underlying defects of diabetes per se from those of obesity and chronic hyperglycemia on the regulation of pulsatile insulin secretion. Serial measurements of insulin secretion and plasma glucose were obtained during 3 standardized mixed meals consumed over 12 h. Insulin secretion rates were calculated by deconvoluting plasma C peptide levels using a mathematical model for C peptide clearance and kinetic parameters derived individually in each subject. Absolute (nadir to peak) and relative (fold increase above nadir) amplitudes of each insulin secretory pulse and glucose oscillation were calculated. Compared to the obese controls, the subclinical and overt NIDDM patients manifested the following abnormal responses: 1) decreased relative amplitudes of insulin pulses, 2) reduced frequency of glucose oscillations, 3) increased absolute amplitudes of glucose oscillations, 4) decreased temporal concomitance between peaks of insulin pulses and glucose oscillations, 5) reduced correlation between the relative amplitudes of glucose oscillations concomitant with insulin pulses, and 6) temporal disorganization of the insulin pulse profiles. These defects were more severe in the overt NIDDM patients, and weight loss only partially reversed these abnormalities in both NIDDM groups. These findings indicate that beta-cell responsiveness is reduced, and the regulation of insulin secretion is abnormal under physiological conditions in all patients with NIDDM, including those without clinical manifestations of the disease. These abnormalities are not completely normalized with weight loss, even in patients who achieve metabolic control comparable to that in obese controls. The results are consistent with the presence of an inherent beta-cell defect that contributes to secretory derangements in subclinical NIDDM patients. This abnormality precedes frank hyperglycemia and may ultimately contribute to the development of overt NIDDM.

    Title Implantable Insulin Pump Vs Multiple-dose Insulin for Non-insulin-dependent Diabetes Mellitus: a Randomized Clinical Trial. Department of Veterans Affairs Implantable Insulin Pump Study Group.
    Date November 1996
    Journal Jama : the Journal of the American Medical Association
    Excerpt

    OBJECTIVE: To determine whether implantable insulin pump (IIP) therapy and multiple daily insulin (MDI) injections could equally attain improved blood glucose control, and to compare the 2 treatments with respect to reducing daily blood glucose fluctuations, reducing serious hypoglycemic insulin reactions, and improving patients' quality of life. DESIGN: Randomized clinical trial. SETTING: Seven Veterans Affairs medical centers. PATIENTS: One hundred twenty-one male type II diabetic patients between the ages of 40 and 69 years, receiving at least 1 injection of insulin per day and having hemoglobin A1c (HbA1c) levels of 8% or above. INTERVENTION: Intensive therapy (IIP or MDI) for 1 year. MAIN OUTCOME MEASURES: Hemoglobin A1c and blood glucose levels. RESULTS: Blood glucose levels declined to 7.96+/-1.08 mmol/L (143.4+/-19.5 mg/dL) and 8.30+/-1.52 mmol/L (149.6+/-27.4 mg/dL) (mean +/- SD) for IIP and MDI, respectively (P=.57). Hemoglobin A1c levels improved in both groups (time effect P<.001), to means of 7.54%+/-0.83% (MDI) vs 7.34%+/-0.79% (IIP). IIP reduced blood glucose fluctuations compared with MDI (P<.001), and reduced the incidence of mild clinical hypoglycemia by 68% (P<.001); IIP also eliminated the weight gain associated with MDI therapy and yielded better overall quality-of-life (P=.03) and impact-of-disease subscale scores (P=.05). Adverse events included 25% of subjects with episodes of insulin underdelivery due to microprecipitates of insulin within the pump. CONCLUSIONS: Intensive insulin therapy with IIP and MDI is effective in controlling non-insulin-dependent diabetes mellitus. IIP has significant advantages in reducing glycemic variability, clinical hypoglycemia, and weight gain, while improving aspects of quality of life.

    Title Glycogen Synthase Activity is Reduced in Cultured Skeletal Muscle Cells of Non-insulin-dependent Diabetes Mellitus Subjects. Biochemical and Molecular Mechanisms.
    Date November 1996
    Journal The Journal of Clinical Investigation
    Excerpt

    To determine whether glycogen synthase (GS) activity remains impaired in skeletal muscle of non-insulin-dependent diabetes mellitus (NIDDM) patients or can be normalized after prolonged culture, needle biopsies of vastus lateralis were obtained from 8 healthy nondiabetic control (ND) and 11 NIDDM subjects. After 4-6 wk growth and 4 d fusion in media containing normal physiologic concentrations of insulin (22 pM) and glucose (5.5 mM), both basal (5.21 +/- 0.79 vs 9.01 +/- 1.25%, P < 0.05) and acute insulin-stimulated (9.35 +/- 1.81 vs 16.31 +/- 2.39, P < 0.05) GS fractional velocity were reduced in NIDDM compared to ND cells. Determination of GS kinetic constants from muscle cells of NIDDM revealed an increased basal and insulin-stimulated Km(0.1) for UDP-glucose, a decreased insulin-stimulated Vmax(0.1) and an increased insulin-stimulated activation constant (A(0.5)) for glucose-6-phosphate. GS protein expression, determined by Western blotting, was decreased in NIDDM compared to ND cells (1.57 +/- 0.29 vs 3.30 +/- 0.41 arbitrary U/mg protein, P < 0.05). GS mRNA abundance also tended to be lower, but not significantly so (0.168 +/- 0.017 vs 0.243 +/- 0.035 arbitrary U, P = 0.08), in myotubes of NIDDM subjects. These results indicate that skeletal muscle cells of NIDDM subjects grown and fused in normal culture conditions retain defects of basal and insulin-stimulated GS activity that involve altered kinetic behavior and possibly reduced GS protein expression. We conclude that impaired regulation of skeletal muscle GS in NIDDM patients is not completely reversible in normal culture conditions and involves mechanisms that may be genetic in origin.

    Title Glucose Transport in Cultured Human Skeletal Muscle Cells. Regulation by Insulin and Glucose in Nondiabetic and Non-insulin-dependent Diabetes Mellitus Subjects.
    Date August 1996
    Journal The Journal of Clinical Investigation
    Excerpt

    A primary human skeletal muscle culture (HSMC) system, which retains cellular integrity and insulin responsiveness for glucose transport was employed to evaluate glucose transport regulation. As previously reported, cells cultured from non-insulin-dependent diabetic (NIDDM) subjects displayed significant reductions in both basal and acute insulin-stimulated transport compared to nondiabetic controls (NC). Fusion/differentiation of NC and NIDDM HSMC in elevated media insulin (from 22 pM to 30 microM) resulted in increased basal transport activities but reduced insulin-stimulated transport, so that cells were no longer insulin responsive. After fusion under hyperinsulinemic conditions, GLUT1 protein expression was elevated in both groups while GLUT4 protein level was unaltered. Fusion of HSMC under hyperglycemic conditions (10 and 20 mM) decreased glucose transport in NC cells only when combined with hyperinsulinemia. Hyperglycemia alone down-regulated transport in HSMC of NIDDM, while the combination of hyperglycemia and hyperinsulinemia had greater effects. In summary: (a) insulin resistance of glucose transport can be induced in HSMC of both NC and NIDDM by hyperinsulinemia and is accompanied by unaltered GLUT4 but increased GLUT1 levels; and (b) HSMC from NIDDM subjects demonstrate an increased sensitivity to impairment of glucose transport by hyperglycemia. These results indicate that insulin resistance in skeletal muscle can be acquired in NC and NIDDM from hyperinsulinemia alone but that NIDDM is uniquely sensitive to the additional influence of hyperglycemia.

    Title Glutamine:fructose-6-phosphate Amidotransferase Activity in Cultured Human Skeletal Muscle Cells: Relationship to Glucose Disposal Rate in Control and Non-insulin-dependent Diabetes Mellitus Subjects and Regulation by Glucose and Insulin.
    Date July 1996
    Journal The Journal of Clinical Investigation
    Excerpt

    We examined the activity of the rate-limiting enzyme for hexosamine biosynthesis, glutamine:fructose-6-phosphate amidotransferase (GFA) in human skeletal muscle cultures (HSMC), from 17 nondiabetic control and 13 subjects with non-insulin-dependent diabetes. GFA activity was assayed from HSMC treated with low (5 mM) or high (20 mM) glucose and low (22 pM) or high (30 microM) concentrations of insulin. In control subjects GFA activity decreased with increasing glucose disposal rate (r = -0.68, P < 0.025). In contrast, a positive correlation existed between GFA and glucose disposal in the diabetics (r = 0.86, P < 0.005). Increased GFA activity was also correlated with body mass index in controls but not diabetics. GFA activity was significantly stimulated by high glucose (22%), high insulin (43%), and their combination (61%). GFA activity and its regulation by glucose and insulin were not significantly different in diabetic HSMC. We conclude that glucose and insulin regulate GFA activity in skeletal muscle. More importantly, our results are consistent with a regulatory role for the hexosamine pathway in human glucose homeostasis. This relationship between hexosamine biosynthesis and the regulation of glucose metabolism is altered in non-insulin-dependent diabetes.

    Title The Expression of Tnf Alpha by Human Muscle. Relationship to Insulin Resistance.
    Date June 1996
    Journal The Journal of Clinical Investigation
    Excerpt

    TNFalpha is orverexpressed in the adipose tissue of obese rodents and humans, and is associated with insulin resistance. To more closely link TNF expression with whole body insulin action, we examined the expression of TNF by muscle, which is responsible for the majority of glucose uptake in vivo. Using RT-PCR, TNF was detected in human heart, in skeletal muscle from humans and rats, and in cultured human myocytes. Using competitive RT-PCR, TNF was quantitated in the muscle biopsy specimens from 15 subjects whose insulin sensitivity had been characterized using the glucose clamp. technique. TNF expression in the insulin resistant subjects and the diabetic patients was fourfold higher than in the insulin sensitive subjects, and there was a significant inverse linear relationship between maximal glucose disposal rate and muscle TNF (r = -0.60, P < 0.02). In nine subjects, muscle cells from vastus lateralis muscle biopsies were placed into tissue culture for 4 wk, and induced to differentiate into myotubes. TNF was secreted into the medium from these cells, and cells from diabetic patients expressed threefold more TNF than cells from nondiabetic subjects. Thus, TNF is expressed in human muscle, and is expressed at a higher level in the muscle tissue and in the cultured muscle cells from insulin resistant and diabetic subjects. These data suggest another mechanism by which TNF may play an important role in human insulin resistance.

    Title Acquired Defects of Glycogen Synthase Activity in Cultured Human Skeletal Muscle Cells: Influence of High Glucose and Insulin Levels.
    Date May 1996
    Journal Diabetes
    Excerpt

    To determine whether defects of muscle glycogen synthase (GS) activity can be acquired by exposure to elevated glucose or insulin levels, human skeletal muscle cells obtained by needle biopsy from normal control subjects were grown in culture for 4-6 weeks followed by 4 days of fusion and differentiation in media containing either normal (5.5 mmol/l glucose and 22 pmol/l insulin) or increased concentrations of glucose (20 mmol/l), insulin (30 micromol/l), or both. After fusion in normal media, acute stimulation by 33 nmol/l insulin for 1 h increased GS fractional velocity (FV) approximately twofold (from 9.01 +/- 1.26 to 16.31 +/- 2.40, P < 0.05). Increasing the media glucose concentration alone to 20 mmol/l during fusion had no effect on basal FV but caused a marginal impairment of the insulin-stimulated GS response (from 8.51 +/- 1.33 to 12.99 +/- 1.90, P = 0.08). Increasing the media insulin concentration to 30 micromol/l during fusion at 5.5 mmol/l glucose also did not alter basal GS FV (10.61 +/- 1.69%) but completely abolished the normal insulin-stimulated increase in GS activity (to 11.63 +/- 1.55%, NS). The combination of high insulin (30 micromol/l) and high glucose (20 mmol/l) during fusion had no greater effect on the FV of either basal (11.66 +/- 2.16%, NS) or insulin-stimulated (9.20 +/- 1.80%, NS) GS activity than high insulin alone. Fusion in hyperinsulinemic media altered the kinetic parameters of GS with a near doubling of the basal Km0.1 and Vmax0.1 for uridinediphospho-glucose. Hyperinsulinemia also totally prevented the normal insulin-stimulated threefold increase in the Vmax0.1 and the 65% decrease in the A0.5 for glucose-6-phosphate. GS mRNA and protein expression, determined by RNase protection assay and immunoblotting, respectively, were unaffected by changes in media conditions. We conclude that exposure of human skeletal muscle cells primarily to high insulin induces severe insulin resistance through multiple acquired posttranslational defects, which affect both the kinetic characteristics and absolute activity of the GS enzyme.

    Title Contribution of Obesity to Defects of Intracellular Glucose Metabolism in Niddm.
    Date March 1996
    Journal Diabetes Care
    Excerpt

    OBJECTIVE--To examine the contribution of obesity to insulin resistance and abnormalities of intracellular glucose and fat metabolism in NIDDM. RESEARCH DESIGN AND METHODS--Glucose turnover measurements and indirect calorimetry were performed in 10 obese non-insulin-dependent diabetes mellitus (NIDDM) and 10 lean NIDDM subjects (body mass index 35.3 +/- 1.0 vs. 24.1 +/- 0.5 kg/m2, P < or = 0.001) in the basal state and during hyperinsulinemic (720 pmol.m-2.min-1) euglycemic (5.0-5.5 mmol/l) clamps. RESULTS--Obese and lean NIDDM subjects demonstrated similar basal rates of glucose uptake (GU) (1.15 +/- 0.08 vs. 1.26 +/- 0.08 mmol/min, NS) as well as oxidative (0.49 +/- 0.07 vs. 0.53 +/- 0.05 mmol/min, NS) and nonoxidative (0.67 +/- 0.10 vs. 0.73 +/- 0.12 mmol/min, NS) glucose metabolism. During hyperinsulinemic glucose clamp studies, rates of GU were lower in obese NIDDM subjects (34.1 +/- 2.3 vs. 55.2 +/- 3.8 mumol.kg fat-free mass [FFM]-1.min-1, P < or = 0.001) as were rates of oxidative (14.1 +/- 1.3 vs. 22.1 +/- 2.1 mumol.kg FFM-1.min-1, P < or = 0.005) and nonoxidative (20.0 +/- 2.3 vs. 33.1 +/- 3.6 mumol.kg FFM-1. min-1, P < or = 0.01) glucose metabolism. Although absolute rates of insulin-stimulated GU were decreased in the obese group, the relative distribution into glucose oxidation (GOX) and nonoxidative glucose metabolism (NOX) was comparable in both groups (GOX 42% in obese and 41% in lean subjects; NOX 58% in obese and 59% in lean subjects). The NIDDM groups had similar basal free fatty acid levels that were suppressed equally during hyperinsulinemic clamps. However, basal fat oxidation (Fox) was greater in the obese NIDDM group (103 +/- 11 vs. 73 +/- 8 mumol/min, P < or = 0.05) and was less suppressed to insulin (74 +/- 13 vs. 16 +/- 3 mumol/min, P < or = 0.001). CONCLUSIONS--These results indicate that when obesity is present in NIDDM subjects with this degree of hyperglycemia, insulin-stimulated GU is lower by 35-40%. Reduced GU in obese NIDDM subjects leads to decreased intracellular substrate availability and lower rates of oxidative and nonoxidative glucose metabolism. Insulin suppression of Fox is also impaired when obesity is present and may contribute to decreased insulin-mediated GU in NIDDM. We conclude that obesity increases insulin resistance in NIDDM primarily by effects on GU rather than the intracellular pathways of glucose metabolism.

    Title Forum One: Current Recommendations About Intensification of Metabolic Control in Non-insulin-dependent Diabetes Mellitus.
    Date February 1996
    Journal Annals of Internal Medicine
    Excerpt

    To review issues about intensive management of non-insulin-dependent diabetes mellitus (NIDDM) and to formulate recommendations for goals and general approaches to implementation of intensive management.

    Title Glucose Control and Insulin Resistance in Non-insulin-dependent Diabetes Mellitus.
    Date February 1996
    Journal Annals of Internal Medicine
    Excerpt

    Chronic hyperglycemia is implicated in the pathogenesis of microvascular, neurologic, and macrovascular complications of diabetes. Recent studies prove that near-normal glycemic control in insulin-dependent diabetes mellitus (IDDM) reduces the risk for the development and progression of microvascular and neurologic complications. With the expectation of comparable benefits, similar glycemic goals have been advocated for the management of non-insulin-dependent diabetes mellitus (NIDDM). However, using intensified insulin therapy to achieve near-normal glycemia in NIDDM may be problematic because of basic differences in pathophysiology of the two types of diabetes. Insulin resistance is a major contributor to the development of hyperglycemia in NIDDM and may prevent attainment of normoglycemia in most patients who are using the conventional approaches of diet, exercise, and oral hypoglycemic therapy. Near-normal glycemia in patients with NIDDM can usually be achieved with exogenous insulin but often requires large doses to overcome the insulin resistance. Intensive insulin therapy normalizes glycemia by decreasing hepatic glucose output and improving peripheral glucose uptake and may also improve insulin resistance and insulin secretion by reducing hyperglycemic glucotoxicity. However, large doses of exogenous insulin are associated with hyperinsulinemia and weight gain, but these effects may be minimized by combining insulin with other forms of therapy, for example, oral antidiabetic agents. When intensive management is instituted, the dose of exogenous insulin should be kept as low as possible. To do this, therapy for NIDDM must be part of a multifaceted approach combining insulin therapy with other effective forms of treatment such as counseling on diet and exercise therapy and the use of oral antidiabetic agents.

    Title Insulin Action and Glucose Metabolism in Nondiabetic Control and Niddm Subjects. Comparison Using Human Skeletal Muscle Cell Cultures.
    Date August 1995
    Journal Diabetes
    Excerpt

    Myoblasts from human skeletal muscle were isolated from needle biopsy samples of vastus lateralis and fused to differentiated multinucleated myotubes. Specific high-affinity insulin and insulin-like growth factor I (IGF-I) binding, glucose transporter proteins GLUT1 and GLUT4, glycogen synthase and pyruvate dehydrogenase proteins, and their specific mRNAs were identified in fused myotubes. Insulin and IGF-I stimulated 2-deoxyglucose uptake twofold with half-maximal stimulation by insulin at 0.98 +/- 0.12 nmol/l and maximal stimulation at 17.5 nmol/l. Acute insulin treatment (33 nmol/l) doubled glycogen synthase activity and glucose incorporation into glycogen while increasing pyruvate dehydrogenase approximately 30%. In cells cultured from NIDDM subjects, both basal (6.9 +/- 1.0 vs. 13.0 +/- 1.7 pmol.mg protein-1.min-1) and acute insulin-stimulated transport (13.5 +/- 2.0 vs. 22.4 +/- 1.3 pmol.mg protein-1.min-1) were significantly reduced compared with nondiabetic control subjects (both P < or = 0.005). GLUT1 protein content of total membranes from NIDDM subjects was decreased compared with control subjects, while GLUT4 levels were similar between groups. A significant correlation (r = 0.65, P < or = 0.05) was present when maximal rates of insulin-stimulated glucose transport in cell culture from subjects were compared with their corresponding in vivo glucose disposal determined by hyperinsulinemic glucose clamp. In summary, differentiated human skeletal muscle cultures exhibit biochemical and molecular features of insulin-stimulated glucose transport and intracellular enzyme activity comparable with the in vivo situation. Defective insulin-stimulated glucose transport persists in muscle cultures from NIDDM subjects and resembles the reduced insulin-mediated glucose uptake present in vivo. We conclude that this technique provides a relevant cellular model to study insulin action and glucose metabolism in normal subjects and determine the mechanisms of insulin resistance in NIDDM.

    Title Impaired Muscle Fat Metabolism: a Cause or Effect of Visceral Obesity?
    Date May 1995
    Journal The Journal of Clinical Investigation
    Title Protein Content of the Diabetic Diet.
    Date April 1995
    Journal Diabetes Care
    Title Role of Basal Insulin in Maintenance of Intracellular Glucose Metabolic Pathways in Non-insulin-dependent Diabetes Mellitus.
    Date March 1995
    Journal Metabolism: Clinical and Experimental
    Excerpt

    Impairments of both basal and insulin-stimulated oxidative (Gox) and nonoxidative (Nox) glucose metabolism are documented to exist in non-insulin-dependent diabetes mellitus (NIDDM). Although these defects have been well characterized during insulin stimulation, little is known about the effects of basal insulin or its deficiency on intracellular glucose metabolism in NIDDM. To determine the physiological significance of basal insulin in the maintenance of glucose metabolism in NIDDM, we studied nine subjects with NIDDM in the basal and insulin-deficient state produced by 3 hours of somatostatin (SRIF) infusion (0.08 pmol/kg/min). Glucose turnover rates were quantified by [3-3H]glucose turnover, and substrate oxidation was assessed by a combination of indirect calorimetry and urinary nitrogen measurements. Skeletal muscle glycogen synthase (GS) and pyruvate dehydrogenase (PDH) activities were also measured in the basal state and during SRIF infusion. Basal glucose levels were maintained during SRIF infusion by exogenous glucose infusion (12.5 +/- 0.9 mmol/L in the basal state v 12.8 +/- 0.8 during SRIF infusion, P = NS). During the last hour of SRIF infusion, plasma C-peptide levels declined by 88% from 0.73 +/- 0.11 to 0.09 +/- 0.02 nmol/L (P < .001), and serum insulin concentrations were undetectable (< 14 pmol/L). During insulinopenic conditions, rates of glucose uptake (GU) were decreased by 12% from basal level of 2.26 +/- 0.13 to 1.99 +/- 0.12 mg/kg/min (P < .05), and were entirely accounted for by reduced rates of Gox (1.01 +/- 0.10 to 0.65 +/- 0.14 mg/kg/min, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Nutrition Principles for the Management of Diabetes and Related Complications.
    Date September 1994
    Journal Diabetes Care
    Title Alterations in Immunoreactive Proinsulin and Insulin Clearance Induced by Weight Loss in Niddm.
    Date July 1994
    Journal Diabetes
    Excerpt

    Subjects with overt non-insulin-dependent diabetes mellitus (NIDDM) were studied in comparison to obese nondiabetic control subjects and patients with subclinical diabetes. Pancreatic insulin secretion rates were measured by deconvolution of peripheral C-peptide over a 24-h period while subjects consumed an isocaloric mixed diet. Subjects were then placed on caloric restriction for at least 6 weeks, during which time body weight fell by at least 10%. Refeeding with solid mixed meals was then resumed for at least 2 weeks until isocaloric intake was attained, and then the meal profiles were repeated. Before weight loss, insulin, C-peptide, and insulin secretion rates were significantly higher in subjects with subclinical diabetes than in the other two groups. Proinsulin concentrations were significantly greater in the two diabetic groups than in control subjects, but, when expressed as a percentage of the total insulin immunoreactivity, the differences were significant only in the group with overt diabetes. Weight loss because of hypocaloric feeding resulted in a significant increase in the rate of clearance of endogenously secreted insulin but did not affect the clearance of C-peptide. In obese subjects and those with subclinical diabetes, weight loss was associated with a reduction in insulin secretion rates, presumably as a result of improvements in insulin sensitivity. In patients with overt diabetes and hyperglycemia, weight loss improved beta-cell responsiveness to glucose and was associated with an increase in insulin clearance and a reduction in proinsulin immunoreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Effects of Varying Carbohydrate Content of Diet in Patients with Non-insulin-dependent Diabetes Mellitus.
    Date June 1994
    Journal Jama : the Journal of the American Medical Association
    Excerpt

    OBJECTIVE--To study effects of variation in carbohydrate content of diet on glycemia and plasma lipoproteins in patients with non-insulin-dependent diabetes mellitus (NIDDM). DESIGN--A four-center randomized crossover trial. SETTING--Outpatient and inpatient evaluation in metabolic units. PATIENTS--Forty-two NIDDM patients receiving glipizide therapy. INTERVENTIONS--A high-carbohydrate diet containing 55% of the total energy as carbohydrates and 30% as fats was compared with a high-monounsaturated-fat diet containing 40% carbohydrates and 45% fats. The amounts of saturated fats, polyunsaturated fats, cholesterol, sucrose, and protein were similar. The study diets, prepared in metabolic kitchens, were provided as the sole nutrients to subjects for 6 weeks each. To assess longer-term effects, a subgroup of 21 patients continued the diet they received second for an additional 8 weeks. MAIN OUTCOME MEASURES--Fasting plasma glucose, insulin, lipoproteins, and glycosylated hemoglobin concentrations. Twenty-four-hour profiles of glucose, insulin, and triglyceride levels. RESULTS--The site of study as well as the diet order did not affect the results. Compared with the high-monounsaturated-fat diet, the high-carbohydrate diet increased fasting plasma triglyceride levels and very low-density lipoprotein cholesterol levels by 24% (P < .0001) and 23% (P = .0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% (P = .03), 12% (P < .0001), and 9% (P = .02), respectively. Plasma total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels remained unchanged. The effects of both diets on plasma glucose, insulin, and triglyceride levels persisted for 14 weeks. CONCLUSIONS--In NIDDM patients, high-carbohydrate diets compared with high-monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable.

    Title Skeletal Muscle Protein Tyrosine Phosphatase Activity and Tyrosine Phosphatase 1b Protein Content Are Associated with Insulin Action and Resistance.
    Date April 1994
    Journal The Journal of Clinical Investigation
    Excerpt

    Particulate and cytosolic protein tyrosine phosphatase (PTPase) activity was measured in skeletal muscle from 15 insulin-sensitive subjects and 5 insulin-resistant nondiabetic subjects, as well as 18 subjects with non-insulin-dependent diabetes mellitus (NIDDM). Approximately 90% of total PTPase activity resided in the particulate fraction. In comparison with lean nondiabetic subjects, particulate PTPase activity was reduced 21% (P < 0.05) and 22% (P < 0.005) in obese nondiabetic and NIDDM subjects, respectively. PTPase1B protein levels were likewise decreased by 38% in NIDDM subjects (P < 0.05). During hyperinsulinemic glucose clamps, glucose disposal rates (GDR) increased approximately sixfold in lean control and twofold in NIDDM subjects, while particulate PTPase activity did not change. However, a strong positive correlation (r = 0.64, P < 0.001) existed between particulate PTPase activity and insulin-stimulated GDR. In five obese NIDDM subjects, weight loss of approximately 10% body wt resulted in a significant and corresponding increase in both particulate PTPase activity and insulin-stimulated GDR. These findings indicate that skeletal muscle particulate PTPase activity and PTPase1B protein content reflect in vivo insulin sensitivity and are reduced in insulin resistant states. We conclude that skeletal muscle PTPase activity is involved in the chronic, but not acute regulation of insulin action, and that the decreased enzyme activity may have a role in the insulin resistance of obesity and NIDDM.

    Title Delayed Onset of Insulin Activation of the Insulin Receptor Kinase in Vivo in Human Skeletal Muscle.
    Date January 1994
    Journal Diabetes
    Excerpt

    During the infusion of insulin in vivo, the rate of activation of glucose disposal lags significantly behind the rate of increase in serum insulin levels. To determine whether this delay was related to transcapillary transport of insulin, we determined increments in serum insulin levels, glucose disposal rates (GDR), and insulin receptor (IR) kinase activity measured during continuous infusions of insulin (40 and 120 mU.m-2.min-1) administered to 8 nondiabetic males; similar studies were done at 1,200.m-2.min-1 in 2 of the subjects. Half-maximal insulin levels were achieved at a mean of 4.9 and 7.2 min during the 40 and 120 mU.m-2.min-1 clamps, respectively, with corresponding half-maximal GDR stimulation at a mean of 59 and 47 min. Unlike the rise in insulin levels, IR kinase activation was much slower with half-maximal activity occurring at approximately 40-60 min in the 2 clamps. Thus, the rise in serum insulin levels in each clamp was much faster than the increment in either kinase activity or glucose disposal. Insulin infusion increased both IR kinase and GDR maximally approximately 10-fold, with half-maximal stimulation at approximately 3,600 and approximately 700 pM, indicating spare kinase for glucose disposal. These results demonstrate that the delay in stimulation of glucose disposal by insulin is related to a rate-limiting step between the intravascular space and the cell-surface of skeletal muscle. This may involve delayed transendothelial transport of insulin.

    Title Intracellular Glucose Metabolism After Long Term Metabolic Control with Glyburide: Improved Glucose Oxidation with Unchanged Glycogen Synthase Activity.
    Date September 1993
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    To determine whether improved metabolic control with long term glyburide treatment alters intracellular glucose metabolism independent of effects on glucose uptake (GU), we studied eight obese patients with noninsulin-dependent diabetes mellitus before and 7 months after glyburide therapy. Indirect calorimetry and skeletal muscle biopsies were performed in the basal state and during 300 pmol/m2.min insulin infusions, with glucose turnover rates determined by [3-3H]glucose turnover. During the glucose clamps, rates of GU were matched before and after treatment using equivalent hyperinsulinemia and variable levels of hyperglycemia. After glyburide treatment, rates of GU were decreased in the basal state [4.16 +/- 0.57 vs. 3.29 +/- 0.37 mg/kg fat free mass (FFM)/min; P < 0.05], but similar during glucose clamps (11.53 +/- 1.42 vs. 11.93 +/- 1.32 mg/kg FFM.min; P = NS) according to study design. In both the basal state and during glucose clamps after glyburide therapy, rates of glucose oxidative metabolism (Gox) increased by 68-78% [1.21 +/- 0.16 vs. 2.03 +/- 0.31 mg/kg FFM.min (P < 0.05) and 3.13 +/- 0.51 vs. 5.58 +/- 0.55 mg/kg FFM.min (P < 0.05), respectively], and rates of nonoxidative glucose metabolism decreased [2.96 +/- 0.68 vs. 1.25 +/- 0.21 mg/kg FFM.min (P < 0.05) and 8.40 +/- 1.50 to 6.30 +/- 1.40 mg/kg FFM.min (P < 0.01), respectively]. Circulating plasma FFA levels and rates of fat oxidation (Fox) remained unchanged in both the basal state and during clamp studies. Skeletal muscle glycogen synthase (GS) activity, expressed as fractional velocity, was unchanged by glyburide therapy (2.2 +/- 0.8 vs. 2.7 +/- 0.3% in the basal state and 7.3 +/- 1.8 vs. 6.1 +/- 0.9% during clamps; both P = NS). In summary, at both matched (during clamp studies) and unmatched (during basal studies) rates of GU, improved metabolic control with glyburide therapy resulted in marked improvement of Gox independent of the effects on GU. The improvement in Gox was not associated with changes in Fox, circulating FFA, or muscle GS activity. These data indicate that long term metabolic control achieved by glyburide therapy markedly improves Gox, but not skeletal muscle GS activity, in noninsulin-dependent diabetes mellitus independent of GU and Fox.

    Title Relative Expression of Insulin Receptor Isoforms Does Not Differ in Lean, Obese, and Noninsulin-dependent Diabetes Mellitus Subjects.
    Date June 1993
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    The insulin receptor is expressed as two isoforms that differ by a 12-amino acid region at the carboxy-terminus of the alpha-subunit encoded by exon 11. These isoforms are produced by tissue-specific alternate splicing of the insulin receptor mRNA. To determine whether the relative expression of the isoforms is altered in skeletal muscle in two insulin-resistant states, NIDDM and obesity, relative mRNA levels were measured using a polymerase chain reaction technique. There were no differences in the relative amounts of skeletal muscle mRNA encoding the exon 11-containing form compared to the exon 11-lacking form of the insulin receptor among lean normal (30 +/- 2% Ex11-), obese nondiabetic (32 +/- 2%), and NIDDM (31 +/- 1%) subjects. We conclude that altered expression of insulin receptor isoform mRNAs does not account for skeletal muscle insulin resistance in NIDDM and obesity.

    Title Intensive Conventional Insulin Therapy for Type Ii Diabetes. Metabolic Effects During a 6-mo Outpatient Trial.
    Date February 1993
    Journal Diabetes Care
    Excerpt

    To determine whether tight glycemic control can be obtained using intensive conventional split-dose insulin therapy in the outpatient management of type II diabetes without development of unacceptable side effects.

    Title Role of Impaired Intracellular Glucose Metabolism in the Insulin Resistance of Aging.
    Date November 1992
    Journal Metabolism: Clinical and Experimental
    Excerpt

    The insulin resistance of aging is characterized by both reduced glucose uptake and impaired intracellular glucose metabolism. The aim of this study was to determine whether impaired intracellular glucose metabolism contributes to insulin resistance in the elderly independent of reduced glucose uptake. To address this question, glucose uptake in non-obese elderly males was matched to controls using the glucose clamp technique, and intracellular glucose metabolism was assessed in vivo by indirect calorimetry and in vitro by skeletal muscle biopsy for glycogen synthase activity. When elderly subjects were compared with controls at an equivalent basal glucose uptake of approximately 2.5 mg/kg fat-free mass (FFM)/min, muscle glycogen synthase activity was similar (fractional velocity of glycogen synthase at 0.1 mmol/L glucose-6-phosphate [FV0.1], 0.06 +/- 0.1 and 0.07 +/- 0.1), but whole-body rates of glucose oxidation were reduced (1.36 +/- 0.12 v 1.90 +/- 0.11 mg/kg FFM/min, P less than .05). During 40-mU/m2/min hyperinsulinemic clamps at matched rates of glucose uptake (approximately 10.7 mg/kg FFM/min in both groups), glycogen synthase activity was again similar (FV0.1, 0.15 +/- 0.02 and 0.14 +/- 0.02), and glucose oxidation remained reduced in the elderly (4.18 +/- 0.25 v 4.77 +/- 0.17 mg/kg FFM/min, P less than .05). Only during clamps in the maximal range of glucose uptake (approximately 29.5 mg/kg FFM/min) was glucose oxidation between the groups comparable (5.97 +/- 0.50 and 5.75 +/- 0.31 mg/kg FFM/min). Plasma free fatty acid (FFA) concentrations, fat oxidation, and protein oxidation were similar under all study conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Why Intraperitoneal Delivery of Insulin with Implantable Pumps in Niddm?
    Date June 1992
    Journal Diabetes
    Excerpt

    In the normal state, pancreatic secretion of insulin results in a portal/peripheral gradient with the highest concentrations of insulin in the liver. In diabetic patients with absent or insufficient pancreatic insulin secretion who require exogenous insulin, this normal gradient is lost, resulting in numerous abnormalities. This consideration led to interest in the intraperitoneal delivery of insulin, hoping to produce a therapeutic state more closely resembling normal physiology. The development of implantable insulin pumps, which can deliver insulin intraperitoneally, led to numerous studies on insulin-dependent diabetes mellitus (IDDM) patients, demonstrating that insulin delivered intraperitoneally is rapidly and predictably absorbed with most of it going into the portal system, resulting in hepatic delivery of insulin. Studies in IDDM patients have demonstrated that good glucose control can be achieved with intraperitoneal delivery of insulin from implantable pumps with lesser glycemic fluctuations and, therefore, fewer episodes of hypoglycemia. Furthermore, intraperitoneal insulin results in carbohydrate and particularly lipid metabolism that more closely mimics the normal physiological state than produced by injections of insulin. Thus, implantable insulin pumps are being studied for use in IDDM. Many non-insulin-dependent diabetes mellitus (NIDDM) patients have insufficient pancreatic secretion and require exogenous insulin. Because of alterations in hepatic sensitivity to insulin, increments in insulin delivery to the liver may be even more important in NIDDM than IDDM. Furthermore, insulin resistance, which is an integral part of NIDDM, results in higher physiological levels of insulin, which are required for glucose control, and thus significant peripheral hyperinsulinemia occurs in patients receiving exogenous insulin.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Advances in Treatment of Type Ii Diabetes Mellitus in the Elderly.
    Date April 1992
    Journal Geriatrics
    Excerpt

    Elderly diabetic patients are prone to the acute and subacute consequences of hyperglycemia, which can adversely affect health, well being, and quality of life. Every elderly patient with diabetes should be offered an individualized treatment plan, consisting of education, dietary counseling, and an exercise program. If fasting and postprandial glucose levels do not stay consistently in the desired range, then an oral hypoglycemic agent should be instituted at the lowest possible dose. When the oral hypoglycemic agent fails, it may be possible to achieve good glycemic control with the addition of insulin. Recent developments in insulin administration can optimize glycemic benefits and reduce potential adverse effects.

    Title Sensitivity of the Mini-mental State Examination to Frontal Lobe Dysfunction in Normal Aging.
    Date April 1992
    Journal Journal of Clinical Psychology
    Excerpt

    The present study examined the sensitivity of the Mini-Mental State Examination (MMSE) in detecting the frontal lobe dysfunction that occurs with normal aging. Eighty normal, independently living older adults in four age groupings from 50 to 89 were administered the MMSE along with three neurocognitive measures sensitive to frontal lobe functioning. Results revealed age-related cognitive decline on frontal lobe tasks that also was detected by the MMSE. These findings are noteworthy because the MMSE was intended as a measure of gross cognitive status rather than of frontal lobe functioning.

    Title Benefits and Limitations of Very-low-calorie Diet Therapy in Obese Niddm.
    Date January 1992
    Journal Diabetes Care
    Excerpt

    Weight reduction is one of the most effective therapies for obese non-insulin-dependent diabetes mellitus (NIDDM), but the success rate with conventional diets has been disappointing. The development of very-low-calorie diets (VLCDs) over the last two decades has provided an alternative approach to the treatment of uncomplicated obesity and is increasingly being used to treat obese NIDDM. This review focuses on the role of VLCDs in the treatment of obese NIDDM, the mechanisms underlying their efficacy, and the controversies surrounding their use. VLCDs provide 400-800 cal/day of high-quality protein and carbohydrate fortified with vitamins, minerals, and trace elements. Weight loss is initially very rapid, followed by steady reduction at a rate of 1-3 kg/wk. Metabolic benefits occur quickly with only modest weight reduction, suggesting that caloric restriction plays a more critical role. Multiple mechanisms account for improved glycemic control, including reduced hepatic glucose output, increased insulin action in the liver and peripheral tissues, and enhanced insulin secretion. VLCDs have the added benefit of rapid improvement in concomitant medical problems, particularly hypertension and hyperlipidemia, that could otherwise accelerate the development of some diabetic complications. Numerous controversies surround VLCD therapy, the most critical of which is its safety. However, recent studies indicate that VLCDs are safe for use by obese NIDDM patients in a medical setting closely supervised by an experienced physician. Contraindications to the diet, side effects, and recommended management are reviewed, as well as the role of adjunctive treatments, including behavioral modification and exercise. We present the perspective that, in most cases, the numerous metabolic benefits derived from VLCD therapy by the obese NIDDM patient outweigh its risks. Furthermore, recent data suggest that VLCD therapy may provide long-term benefits to the obese diabetic patient, despite weight regain.

    Title Analysis of the Gene Sequences of the Insulin Receptor and the Insulin-sensitive Glucose Transporter (glut-4) in Patients with Common-type Non-insulin-dependent Diabetes Mellitus.
    Date October 1991
    Journal The Journal of Clinical Investigation
    Excerpt

    Insulin resistance is a common feature of non-insulin-dependent diabetes mellitus (NIDDM) and "diabetes susceptibility genes" may be involved in this abnormality. Two potential candidate genes are the insulin receptor (IR) and the insulin-sensitive glucose transporter (GLUT-4). To elucidate whether structural defects in the IR and/or GLUT-4 could be a primary cause of insulin resistance in NIDDM, we have sequenced the entire coding region of the GLUT-4 gene from DNA of six NIDDM patients. Since binding properties of the IRs from NIDDM subjects are normal, we also analyzed the sequence of exons 16-22 (encoding the entire cytoplasmic domain of the IR) of the IR gene from the same six patients. When compared with the normal IR sequence, no difference was found in the predicted amino acid sequence of the IR cytoplasmic domain derived from the NIDDM patients. Sequence analysis of the GLUT-4 gene revealed that one patient was heterozygous for a mutation in which isoleucine (ATC) was substituted for valine (GTC) at position 383. Consequently, the GLUT-4 sequence at position 383 was determined in 24 additional NIDDM patients and 30 nondiabetic controls and all showed only the normal sequence. From these studies, we conclude that the insulin resistance seen in the great majority of subjects with the common form of NIDDM is not due to genetic variation in the coding sequence of the IR beta subunit, nor to any single mutation in the GLUT-4 gene. Possibly, a subpopulation of NIDDM patients exists displaying variation in the GLUT-4 gene.

    Title Current Issues in Fructose Metabolism.
    Date October 1991
    Journal Annual Review of Nutrition
    Excerpt

    The ingestion of fructose, particularly in refined form, has significantly increased in the North American diet over the last two decades. The unique way in which fructose is metabolized has given rise to much research examining whether fructose is advantageous in appetite control, exercise endurance, and disease states such as diabetes. Overall, there is very little evidence that modest amounts of fructose have detrimental effects on carbohydrate and lipid metabolism in nondiabetic or NIDDM subjects or that its use is particularly advantageous compared to that of other sugars. However, fructose can cause insulin and triglyceride levels to rise dramatically, and hence be potentially harmful, in a subgroup of NIDDM subjects who have concomitant pronounced hypertriglyceridemia. Large doses of fructose should also be avoided by subjects with gout because of the hyperuricemia which may result. No evidence exists that fructose has any clear advantages over glucose in regard to exercise endurance. Similarly there is no conclusive evidence that physiologic amounts of dietary fructose exacerbate copper deficiency or aid in weight control.

    Title Dose-response Characteristics of Impaired Glucose Oxidation in Non-insulin-dependent Diabetes Mellitus.
    Date August 1991
    Journal The American Journal of Physiology
    Excerpt

    To determine the dose-response characteristics of impaired glucose oxidation in non-insulin-dependent diabetes mellitus (NIDDM), indirect calorimetry was performed on eight matched control and NIDDM subjects during the basal state and during three glucose clamps at insulin infusion rates of 150, 300, and 1,500 pmol.m-2.min-1. Hyperglycemia was used to achieve matched rates of glucose uptake at each insulin infusion. Glucose uptake in the basal state was greater in NIDDM [3.75 +/- 0.23 vs. 2.50 +/- 0.10 mg.kg fat-free mass (FFM)-1.min-1, P less than 0.005] but was similar at approximately 8, 12, and 26 mg.kg FFM-1.min-1 at each insulin infusion. Basal protein oxidation, fat oxidation, and plasma free fatty acids were similar and equally sensitive to suppression by insulin in both groups. Glucose oxidation was reduced 20-26%, and circulating lactate increased 50-90% at physiological but not at pharmacological insulin concentrations in NIDDM. The dose-response relationship between serum insulin and glucose oxidation was right shifted in NIDDM with half-maximal activation at 368 +/- 91 vs. 179 +/- 27 pM in controls (P less than 0.05). In conclusion, glucose oxidation is reduced at physiological insulin concentrations in NIDDM and cannot be explained by concomitant obesity, increased fat oxidation, or reduced glucose uptake but results from impaired sensitivity to stimulation by insulin, possibly at pyruvate dehydrogenase.

    Title In Vivo Stimulation of the Insulin Receptor Kinase in Human Skeletal Muscle. Correlation with Insulin-stimulated Glucose Disposal During Euglycemic Clamp Studies.
    Date July 1991
    Journal The Journal of Clinical Investigation
    Excerpt

    To assess the relationship between insulin receptor (IR) kinase activity and insulin action in vivo in humans, we measured glucose disposal rates (GDR) during a series of euglycemic clamp studies. Simultaneously, we measured IR kinase activity in IRs extracted from skeletal muscle obtained by needle biopsy at the end of each clamp. By preserving the phosphorylation state of the receptors as it existed in vivo at the time of biopsy, we could correlate GDR and IR kinase in skeletal muscle. Eight nondiabetic, nonobese male subjects underwent studies at insulin infusion rates of 0, 40, 120, and 1,200 mU/m2 per min. Kinase activity, determined with receptors immobilized on insulin agarose beads, was measured at 0.5 microM ATP, with 1 mg/ml histone, followed by SDS-PAGE. Insulin increased GDR approximately sevenfold with a half-maximal effect at approximately 100 microU/ml insulin and a maximal effect by approximately 400 microU/ml. Insulin also increased IR kinase activity; the half-maximal effect occurred at approximately 500-600 microU/ml insulin with a maximal 10-fold stimulation over basal. Within the physiologic range of insulin concentrations, GDR increased linearly with kinase activation (P less than 0.0006); at supraphysiologic insulin levels, this relationship became curvilinear. Half-maximal and maximal insulin-stimulated GDR occurred at approximately 20 and approximately 50% maximal kinase activation, respectively. These results are consistent with a role of the kinase in insulin action in vivo. Furthermore, they demonstrate the presence of a large amount of "spare kinase" for glucose disposal.

    Title Substrate Oxidation Errors During Combined Indirect Calorimetry-hyperinsulinemic Glucose Clamp Studies.
    Date May 1991
    Journal Metabolism: Clinical and Experimental
    Excerpt

    The procedure of indirect calorimetry is often combined with the hyperinsulinemic, euglycemic clamp technique so that intracellular rates of glucose oxidation (Gox), fat oxidation (Fox), and energy expenditure (EE) can be determined at different insulin concentrations and rates of whole-body glucose uptake. In order to perform these calculations, rates of protein oxidation (Pox) must be known and are usually estimated from urinary nitrogen (N) excretion. The use of urinary N assumes that this measurement accurately reflects Pox and is unaltered by the glucose clamp technique. To examine these assumptions and determine potential errors in rates of Gox, Fox, and EE with this method, eight healthy subjects each had basal urinary N excretion determined on 4 different days and during a 300 pmol/m2/min hyperinsulinemic, euglycemic clamp. Mean basal urinary N excretion was 6.4 +/- 1.6 mg/min. Within individuals, basal urinary N was highly variable on the 4 different days with a mean coefficient of variation (CV) of 36% +/- 18%. Over the range of basal respiratory quotient (RQ) values in this study (0.78 to 0.85) the day-to-day variation in basal urinary N resulted in potential errors of 11% to 23% for Gox, 16% to 24% for Fox, but minimal effects (less than or equal to 1%) on EE. During the hyperinsulinemic, euglycemic clamp, RQ increased to 0.95 or greater, while urinary N excretion, rather than decreasing as expected, increased by 47% (6.4 +/- 1.6 to 9.4 +/- 2.8 mg/min) due in part to increases in urea clearance from 37.5 +/- 6.7 to 75.2 +/- 12.4 mL/min (P less than .025). This increased urinary N excretion had minimal influence on Fox and EE, but underestimated Gox by up to 5% at RQ less than 0.95. A more accurate estimate of urinary N excretion during hyperinsulinemic clamps may be obtained by correcting for changes in urea clearance. These results indicate that basal urinary N excretion is highly variable and influenced by hyperinsulinemic glucose clamps. Thus, urinary N excretion, particularly during the basal state, may not accurately reflect changes in Pox and can lead to substantial errors in Gox and Fox.

    Title Reduced Glucose-induced Thermogenesis is Present in Noninsulin-dependent Diabetes Mellitus Without Obesity.
    Date April 1991
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    Decreased glucose-induced thermogenesis has been observed in all forms of obesity. However, some studies implicate insulin resistance rather than obesity per se as the mechanism by which glucose-induced thermogenesis is reduced. To establish the role of insulin resistance in reduced thermogenesis independent of obesity, we compared energy expenditure in 9 nonobese individuals with noninsulin-dependent diabetes mellitus (NIDDM) to 16 nonobese control subjects using indirect calorimetry and the hyperinsulinemic clamp technique. To document the presence of insulin resistance and reduced glucose-induced thermogenesis in nonobese NIDDM, 6 individuals from each group were studied under identical conditions of hyperinsulinemia (120 mU/m2.min) and euglycemia (approximately 5 mmol/l). Both glucose uptake (0.482 +/- 0.042 vs. 0.737 +/- 0.040 g/min) and energy expenditure above basal (0.04 +/- 0.02 vs. 0.10 +/- 0.02 kcal/min) were decreased in nonobese NIDDM compared to control subjects (both P less than 0.05). To determine whether decreased glucose-induced thermogenesis could be overcome by correcting for reduced glucose uptake, the 9 nonobese NIDDM individuals were age and weight-matched to 9 control subjects and clamps were performed at matched rates of glucose uptake. During a 40 mU/m2.min insulin infusion, the nonobese NIDDM individuals were studied at hyperglycemia (17.5 +/- 1.9 mmol/L) and compared to the control subjects at euglycemia (5.1 +/- 0.1 mmol/L; P less than 0.05). Under these conditions, both groups achieved similar rates of glucose uptake (0.698 +/- 0.040 vs. 0.688 +/- 0.038 g/min, NIDDM and control subjects, respectively) and similar rates of energy expenditure above basal (0.08 +/- 0.03 vs. 0.06 +/- 0.02 kcal/min, P = NS). During 600 mU/m2.min clamps performed at hyperglycemia (19.0 +/- 1.2 vs. 14.5 +/- 1.1 mmol/L, NIDDM vs. control subjects, respectively; P less than 0.05), rates of maximal glucose uptake (1.538 +/- 0.093 vs. 1.518 +/- 0.047 g/min) and energy expenditure above basal (0.34 +/- 0.03 vs. 0.31 +/- 0.03 kcal/min) were also similar (P = NS). In conclusion nonobese NIDDM is associated with both decreased rates of glucose uptake and decreased glucose-induced thermogenesis. Decreased glucose substrate availability, due to impaired insulin action, appears to be the critical determinant of glucose-induced thermogenesis in nonobese NIDDM. These data indicate that decreased thermogenesis in NIDDM is a consequence of insulin resistance and can occur independent of obesity.

    Title Multiple Defects in Muscle Glycogen Synthase Activity Contribute to Reduced Glycogen Synthesis in Non-insulin Dependent Diabetes Mellitus.
    Date March 1991
    Journal The Journal of Clinical Investigation
    Excerpt

    To define the mechanisms of impaired muscle glycogen synthase and reduced glycogen formation in non-insulin dependent diabetes mellitus (NIDDM), glycogen synthase activity was kinetically analyzed during the basal state and three glucose clamp studies (insulin approximately equal to 300, 700, and 33,400 pmol/liter) in eight matched nonobese NIDDM and eight control subjects. Muscle glycogen content was measured in the basal state and following clamps at insulin levels of 33,400 pmol/liter. NIDDM subjects had glucose uptake matched to controls in each clamp by raising serum glucose to 15-20 mmol/liter. The insulin concentration required to half-maximally activate glycogen synthase (ED50) was approximately fourfold greater for NIDDM than control subjects (1,004 +/- 264 vs. 257 +/- 110 pmol/liter, P less than 0.02) but the maximal insulin effect was similar. Total glycogen synthase activity was reduced approximately 38% and glycogen content was approximately 30% lower in NIDDM. A positive correlation was present between glycogen content and glycogen synthase activity (r = 0.51, P less than 0.01). In summary, defects in muscle glycogen synthase activity and reduced glycogen content are present in NIDDM. NIDDM subjects also have less total glycogen synthase activity consistent with reduced functional mass of the enzyme. These findings and the correlation between glycogen synthase activity and glycogen content support the theory that multiple defects in glycogen synthase activity combine to cause reduced glycogen formation in NIDDM.

    Title Metabolic Effects of Hyperglycemia and Hyperinsulinemia on Fate of Intracellular Glucose in Niddm.
    Date December 1990
    Journal Diabetes
    Excerpt

    Hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) stimulates peripheral glucose uptake, which tends to compensate for impaired insulin-mediated glucose uptake. The metabolic fate of glucose and suppression of fat oxidation may differ, however, when glucose uptake is stimulated primarily by insulin or hyperglycemia. To address this issue, three hyperinsulinemic glucose-clamp studies were performed in combination with indirect calorimetry in seven nonobese subjects with NIDDM. In the first two experiments, when glucose uptake was matched at approximately 8 mg.kg-1 fat-free mass (FFM).min-1 with primarily hyperinsulinemia (1350 +/- 445 pM) or hyperglycemia (20.8 +/- 1.8 mM), identical rates of glucose oxidation (3.21 +/- 0.29 and 3.10 +/- 0.23 mg.kg-1 FFM.min-1, NS) and nonoxidative glucose metabolism (5.19 +/- 0.75 and 5.46 +/- 0.61 mg.kg-1 FFM.min-1, NS) were achieved. When glucose uptake was increased further to 11.11 +/- 0.36 mg.kg-1 FFM.min-1 with less insulin (625 +/- 70 pM) and hyperglycemia, glucose oxidation (3.85 +/- 0.26 mg.kg-1 FFM.min-1) and nonoxidative glucose metabolism (7.26 +/- 0.51 mg.kg-1 FFM.min-1) rose significantly (both P less than 0.05 from matched studies at lower rates of glucose uptake). During all glucose-clamp studies, free fatty acids were comparably suppressed by 40-46% (all P less than 0.005 vs. basal values), whereas fat oxidation was suppressed by 70-80% (all P less than 0.005 vs. basal values). A strong negative correlation was observed between rates of glucose and fat oxidation (r = -0.88, P less than 0.001) when all studies were combined.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Effect of Hyperinsulinemia and Hyperglycemia on Intracellular Glucose and Fat Metabolism in Healthy Subjects.
    Date November 1990
    Journal Diabetes
    Excerpt

    Hyperinsulinemia and hyperglycemia per se both stimulate glucose uptake and the disposal of glucose by oxidative (Gox) and nonoxidative (Nox) metabolism. However, the intracellular metabolic fate of glucose may not be the same when glucose uptake is stimulated predominantly by either of these mechanisms due to different effects on fat oxidation (Fox). To address this issue, 11 healthy subjects each had four glucose-clamp studies performed in combination with indirect calorimetry to compare Gox, Nox, and Fox at two different rates of glucose uptake (approximately 7 and 10 mg.kg-1 fat-free mass [FFM].min-1) matched at each level by either hyperglycemia or hyperinsulinemia. When glucose uptake was matched at the lower rate (7 mg.kg-1 FFM.min-1), there was less suppression of both FFA (33 vs. 43%, P less than 0.05) and Fox (73 vs. 90%, P less than 0.05) and less stimulation of incremental (above basal) Gox (1.95 vs. 2.49 mg.kg-1 FFM.min-1, P less than 0.025) at low insulin (72 pM) and hyperglycemia (21.8 mM) compared with high insulin (280 pM) and euglycemia (5.1 mM). Matching glucose uptake at the higher rates (10 mg.kg-1 FFM.min-1) required greater than 300 pM of insulin (309 and 632 pM) in both studies and resulted in maximal suppression of FFA (49 vs. 46%, NS) and Fox (both greater than 90%, NS) and similar incremental Gox (2.89 vs. 2.73 mg.kg-1 FFM.min-1, NS) whether at hyperglycemia (15.7 mM) or euglycemia (5.2 mM). Therefore, both hyperinsulinemia and hyperglycemia stimulate glucose uptake and increase intracellular glucose availability, but insulin also regulates Gox by suppression of FFA and Fox. However, when FFA and Fox are maximally suppressed, the rate of glucose uptake, rather than the prevailing insulin level, determines the distribution of intracellular glucose metabolism.

    Title Effects of Ketone Bodies on Carbohydrate Metabolism in Non-insulin-dependent (type Ii) Diabetes Mellitus.
    Date September 1990
    Journal Metabolism: Clinical and Experimental
    Excerpt

    The ability of ketone bodies to suppress elevated hepatic glucose output was investigated in eight postabsorptive subjects with non-insulin-dependent diabetes mellitus (NIDDM). Infusion of sodium acetoacetate alone (20 mumols/kg/min) for 3 hours increased total serum ketones (beta-hydroxybutyrate and acetoacetate) to approximately 6 mmol/L, but did not reduce plasma glucose (14.0 +/- 0.8 to 12.3 +/- 0.9 mmol/L) or isotopically determined hepatic glucose output (17.5 +/- 1.4 to 12.7 +/- 1.0 mumols/kg/min) more than saline alone. Plasma C-peptide concentrations were unchanged, while serum glucagon increased from 131 +/- 13 to 169 +/- 24 ng/mL (P less than .015) and free fatty acids were suppressed by 43% (0.35 +/- 0.08 to 0.20 +/- 0.06 mmol/L, P less than .025). When sodium acetoacetate was infused with somatostatin (0.10 micrograms/kg/min) to suppress glucagon and insulin secretion, the decrease in both plasma glucose (13.3 +/- 0.9 to 10.2 +/- 0.7 mmol/L) and hepatic glucose output (17.2 +/- 1.6 to 9.4 +/- 0.6 mumols/kg/min) was greater than either acetoacetate or somatostatin infusion alone. Infusion of equimolar amounts of sodium bicarbonate had no effect on glucose metabolism. In conclusion, these results demonstrate that ketone bodies can directly suppress elevated hepatic glucose output in NIDDM independent of changes in insulin secretion, but only when the concomitant stimulation of glucagon secretion is prevented. Ketone bodies also suppress adipose tissue lipolysis in the absence of changes in plasma insulin and may serve to regulate their own production.

    Title Effects of Weight Loss and Reduced Hyperglycemia on the Kinetics of Insulin Secretion in Obese Non-insulin Dependent Diabetes Mellitus.
    Date July 1990
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    Impairment in pancreatic production of insulin, a cardinal feature of noninsulin dependent diabetes mellitus (NIDDM), was quantified and the kinetics of insulin secretion characterized in six obese individuals with NIDDM before and after weight loss (18.0 +/- 3.0 kg, mean +/- SEM) using a validated mathematical model that employs C-peptide as a marker of the in vivo rate of insulin secretion. The metabolic clearance of C-peptide, assessed by decay analysis after bolus injection of biosynthetic human C-peptide, was not changed by weight loss (0.143 +/- 0.009 L/min.m2 vs. 0.137 +/- 0.010 L/min.m2). Kinetic parameters from each individual's decay curve before and after weight loss were used to derive accurate rates of secretion during the basal (postabsorptive) state, an oral glucose tolerance test and two hyperglycemic clamps. Basal rates of insulin secretion declined 20 +/- 5 pmol/min.m2 (96 +/- 15 to 76 +/- 15 pmol/min.m2, P less than 0.05) concomitant with decreases of 6.9 +/- 0.9 mmol/L in fasting serum glucose (13.7 +/- 1.0 to 6.8 +/- 0.7 mmol/L, P less than 0.05), 60 +/- 14 pmol/L in serum insulin (134 +/- 30 to 74 +/- 15 pmol/L, P less than 0.05), and 0.15 +/- 0.03 pmol/ml in plasma C-peptide (0.67 +/- 0.11 to 0.52 +/- 0.08 pmol/ml, P less than 0.05) concentrations. As expected, weight loss resulted in improved glucose tolerance as measured by the glycemic profiles during the oral glucose tolerance test (P less than 0.05 analysis of variance). The insulin secretory response before weight loss showed a markedly reduced ability to respond appropriately to an increase in the ambient serum glucose. After weight loss, the pancreatic response was more dynamic (P less than 0.05, analysis of variance) and parralleled the moment-to-moment changes in glycemia. Insulin production above basal doubled (11.2 +/- 3.2 to 24.5 +/- 5.8 nmol/6h.m2, P less than 0.05) and peak rates of insulin secretion above basal tripled (55 +/- 16 to 157 +/- 32 pmol/min/m2, P less than 0.05). To assess the beta-cell response to glucose per se and the changes associated with weight reduction, two hyperglycemic clamps were performed at steady state glucose levels in the range characteristic of individuals with severe NIDDM. At a fixed glycemia of 20 mmol/L, average rates of insulin secretion increased almost 2-fold with treatment (161 +/- 41 to 277 +/- 60 pmol/min.m2, P less than 0.05). At an increment of 6 mmol/L glucose above prevailing fasting glucose levels, the average rate of insulin secretion increased 53% (120 +/- 21 to 183 +/- 39 pmol/min.m2, P less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

    Title Intracellular Glucose Oxidation and Glycogen Synthase Activity Are Reduced in Non-insulin-dependent (type Ii) Diabetes Independent of Impaired Glucose Uptake.
    Date March 1990
    Journal The Journal of Clinical Investigation
    Excerpt

    To examine whether reduced rates of oxidative (Gox) and non-oxidative (Nox) glucose metabolism in non-insulin-dependent diabetes mellitus (NIDDM) are due to reduced glucose uptake, intrinsic defects in intracellular glucose metabolism or increased fat oxidation (Fox), indirect calorimetry was performed at similar glucose uptake rates in eight nonobese NIDDM and eight comparable nondiabetic subjects. Three glucose clamp studies were performed: one in the nondiabetic and two in the NIDDM subjects. In the nondiabetic subjects, glucose uptake was increased to 7.62 +/- 0.62 mg/kg of fat-free mass (FFM) per min by increasing serum insulin to 309 pmol/liter at a glucose concentration of 5.1 mmol/liter. By raising the concentration of either serum glucose or insulin fourfold in the NIDDM subjects, glucose uptake was matched to nondiabetic subjects (8.62 +/- 0.49 and 8.59 +/- 0.51 mg/kg FFM per min, respectively, P = NS). Skeletal muscle glycogen synthase activity and plasma lactate levels were measured to characterize Nox. When glucose uptake was matched to nondiabetics by hyperglycemia or hyperinsulinemia, Gox was reduced by 26-28% in NIDDM (P less than 0.025) whereas Fox was similar. Nox was greater in NIDDM (P less than 0.01) and was accompanied by increases in circulating lactate levels. Glycogen synthase activity was reduced by 41% (P less than 0.025) when glucose uptake was matched by hyperglycemia. Glycogen synthase activity was normalized in NIDDM, however, when glucose uptake was matched by hyperinsulinemia. Therefore, a defect in Gox exists in nonobese NIDDM subjects which cannot be overcome by increasing glucose uptake or insulin. Since both glucose uptake and Fox were similar in the two subject groups these factors were not responsible for reduced Gox. Increased Nox in NIDDM is primarily into lactate. Reduced glycogen synthase activity in NIDDM is independent of glucose uptake but can be overcome by increasing the insulin concentration.

    Title Long-term Effects of Dietary Fructose on Carbohydrate Metabolism in Non-insulin-dependent Diabetes Mellitus.
    Date February 1990
    Journal Metabolism: Clinical and Experimental
    Excerpt

    The effect of dietary fructose on glycemic control in subjects with diabetes mellitus is controversial. Therefore our aim was to conduct a long-term study to examine the effects of dietary fructose on glucose tolerance and insulin sensitivity and to delineate the mechanisms for the effects observed. Six subjects with non-insulin-dependent diabetes mellitus (NIDDM) who were being treated by diet alone consumed 13% of their calories as fructose incorporated into mixed meals in place of sucrose for 3 months as inpatients on a metabolic ward. The following parameters were measured: (1) weekly fasting plasma-glucose concentrations, (2) postprandial serum glucose and insulin levels after four sugar tolerance tests, (3) basal hepatic glucose production, and (4) hepatic and whole-body insulin sensitivity determined during a hyperinsulinemic, euglycemic clamp. When modest amounts of fructose were substituted for sucrose in the diet for 3 months, basal hepatic glucose output remained unchanged (12.84 +/- 1.83 nmol/kg/min v 12.51 +/- 2.00 nmol/kg/min) as did hepatic insulin sensitivity (92% +/- 4% v 93% +/- 4% suppression) and peripheral glucose disposal (22.52 +/- 4.56 nmol/kg/min v 25.80 +/- 9.45 nmol/kg/min) to a 860 pmol/m2/min insulin infusion at euglycemia (4.8 mmol/L). Fructose feeding also did not alter fasting plasma-glucose concentrations or postprandial plasma glucose and insulin responses to oral glucose or fructose loads or to mixed meals containing either sucrose or fructose. In conclusion, substitution of physiologic amounts of sucrose by fructose for prolonged periods is unlikely to have adverse effects on glucose metabolism in diabetic subjects who are being treated with diet alone.

    Title Lipid Metabolism in Non-insulin-dependent Diabetes: Effects of Long-term Treatment with Fructose-supplemented Mixed Meals.
    Date December 1989
    Journal The American Journal of Clinical Nutrition
    Excerpt

    Using fructose in the diabetic diet remains controversial primarily because of the potential for adverse effects on serum lipids. Therefore, lipid metabolism was evaluated in five NIDDM subjects (as inpatients) for 3 mo before and after ingestion of mixed meals containing 13% of calories as fructose. Triglyceride (TG) transport in very-low-density lipoproteins (VLDL) was assessed by multicompartmental analysis of VLDL-TG specific activity after injection of 3H-2-glycerol. There were no deleterious changes in lipid metabolism after fructose supplementation. The fructose diet produced no changes in serial free fatty acids (from 0.39 +/- 0.04 to 0.51 to 0.12 mmol/L), total cholesterol (from 5.43 +/- 0.52 to 5.53 +/- 0.57 mmol/L), high-density lipoproteins (from 0.91 +/- 0.08 to 0.93 +/- 0.08 mmol/L), low-density lipoproteins (from 3.10 +/- 0.52 to 2.92 +/- 0.47 mmol/L), VLDL-TG production (from 2.11 +/- 0.36 to 2.07 +/- 0.30 mmol/h), and fractional catabolic rate (from 0.186 +/- 0.014 to 0.196 +/- 0.03/h). Physiologic amounts of fructose are unlikely to have adverse effects on lipid metabolism when consumed by these diabetic subjects in place of sucrose in mixed meals for a prolonged period.

    Title Mechanism of Defective Insulin-receptor Kinase Activity in Niddm. Evidence for Two Receptor Populations.
    Date April 1989
    Journal Diabetes
    Excerpt

    We used anti-insulin-receptor and anti-phosphotyrosine antibodies to elucidate the mechanism of decreased insulin-receptor tyrosine kinase activity observed in subjects with non-insulin-dependent diabetes mellitus (NIDDM). Lectin-purified insulin receptors were labeled with 125I-labeled NAPA-DP-insulin and autophosphorylated in the presence of 500 microM unlabeled ATP. Immunoprecipitation occurred in 43 +/- 8% of the autophosphorylated, 125I-labeled receptors from nondiabetic subjects with anti-phosphotyrosine antibodies in contrast to 100% immunoprecipitation with anti-insulin-receptor antibodies. Anti-phosphotyrosine antibodies immunoprecipitated only 14 +/- 6% of NIDDM receptors (P less than .05 vs. nondiabetic receptors). A significant correlation existed between maximal insulin-stimulated receptor tyrosine kinase activity and the proportion of receptors immunoprecipitated by anti-phosphotyrosine antibodies (r = .76, P less than .01). These results suggest that human adipocytes contain two distinct receptor populations, both of which bind insulin but only one of which is capable of insulin-stimulated tyrosine phosphorylation. In nondiabetic subjects, 40-50% of the receptors that bind insulin are capable of insulin-stimulated tyrosine autophosphorylation. The proportion of receptors that bind insulin but are incapable of insulin-stimulated tyrosine autophosphorylation is increased in NIDDM; the magnitude of this increase correlated with the magnitude of the decrease in kinase activity.

    Title Cellular Mechanisms of Insulin Resistance in Non-insulin-dependent (type Ii) Diabetes.
    Date December 1988
    Journal The American Journal of Medicine
    Excerpt

    Recent studies have led to an enhanced understanding of cellular alterations that may play an important role in the pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM). The insulin receptor links insulin binding at the cell surface to intracellular activation of insulin's effects. This transducer function involves the tyrosine kinase property of the beta-subunit of the receptor. It was found that adipocytes from subjects with NIDDM had a 50 to 80 percent reduction in insulin-stimulated receptor kinase activity compared with their non-diabetic counterparts. This defect was relatively specific for the diabetic state since no decrease was observed in insulin-resistant non-diabetic obese subjects. The reduction in kinase activity was accounted for by changes in the ratio of two pools of receptors, both of which bind insulin but only one of which is capable of tyrosine autophosphorylation and subsequent kinase activation; 43 percent of the receptors from non-diabetic subjects were capable of autophosphorylation compared with only 14 percent in the NIDDM group. A major component of cellular insulin resistance in NIDDM involves the glucose transport system. Exposure of cells to insulin normally results in enhanced glucose transport mediated by translocation of glucose transporters from a low-density microsomal intracellular pool to the plasma membrane. It was found that cells from NIDDM subjects had a marked depletion of glucose transporters in both plasma membranes and low-density microsomes, relative to obese non-diabetic control participants. Obese non-diabetic persons had a normal number of plasma membrane transporters but a reduced number of low-density microsome transporters in the basal state compared with lean control volunteers; insulin induced the translocation of relatively fewer transporters from the low-density microsome to the plasma membrane in the obese subgroups. In addition to the diminished number of glucose transporters, cells from both NIDDM and obese subjects had impaired functional activity of glucose carriers since decreased whole-cell glucose transport rates could not be entirely explained by the magnitude of the decrement in the number of plasma membrane transporters. Thus, impaired glucose transport is due to both a numerical and functional defect in glucose transporters. The cellular content of high-density microsomal transporters was the same in lean and obese control volunteers and NIDDM subjects, suggesting that transporter synthesis is normal and that cellular depletion results from increased protein turnover once transporters leave the high-density microsomal subfraction.(ABSTRACT TRUNCATED AT 400 WORDS)

    Title Reversibility of Defective Adipocyte Insulin Receptor Kinase Activity in Non-insulin-dependent Diabetes Mellitus. Effect of Weight Loss.
    Date November 1988
    Journal The Journal of Clinical Investigation
    Excerpt

    Insulin-stimulated kinase activity of adipocyte-derived insulin receptors is reduced in subjects with non-insulin-dependent diabetes mellitus (NIDDM) but normal in obese nondiabetics. To assess the reversibility of the kinase defect in NIDDM, insulin receptor kinase activity was measured before and after weight loss in 10 NIDDM and 5 obese nondiabetic subjects. Peripheral insulin action was also assessed in vivo by glucose disposal rates (GDR) measured during a hyperinsulinemic (300 mU/M2 per min) euglycemic clamp. In the NIDDMs, insulin receptor kinase activity was reduced by 50-80% and rose to approximately 65-90% (P less than 0.01) of normal after 13.2 +/- 2.0 kg (P less than 0.01) weight loss; comparable weight loss (18.2 +/- 1.5 kg, P less than 0.01) in the nondiabetics resulted in no significant change in insulin receptor kinase activity. Relative to GDR measured in lean nondiabetics, GDR in the NIDDMs was 35% of normal initially and 67% (P less than 0.01) of normal after diet therapy; weight loss in the nondiabetics resulted in an increase in GDR from 53 to 76% of normal (P less than 0.05). These results indicate that the insulin receptor kinase defect that is present in NIDDM is largely reversible after weight reduction. In contrast, the improvement in GDR, in the absence of any change in insulin receptor kinase activity in the nondiabetics, suggests that the main cause of insulin resistance in obesity lies distal to the kinase.

    Title Functional and Structural Differences in Human and Rat-derived Insulin Receptors: Characterization of the Beta-subunit Kinase Activity.
    Date October 1988
    Journal Endocrinology
    Excerpt

    We studied the kinase activity of partially purified insulin receptor preparations from various rat and human tissues. Time courses for in vitro autophosphorylation were determined, and times to reach half-maximal (t1/2 max) and maximal (tmax) 32P incorporation were compared. Insulin receptors from rat muscle, liver, and fat had a t1/2 max of 7-10 min and a tmax of 60 min; human-derived insulin receptors had a t1/2 max in excess of 30 min and a tmax of 120 min. A spectrum of autophosphorylation time courses was present in human tissues; placenta-derived receptors exhibited a t1/2 max of 13 min while receptors from monocytes and fibroblasts had t1/2 max values of 60 and 80 min, respectively. The ATP Km for autophosphorylation of human-derived receptors was 5-fold greater than that of rat-derived receptors (266 +/- 27 vs. 48 +/- 8 microM, respectively). In contrast, when the receptors were first maximally prephosphorylated, the ATP Km values for substrate phosphorylation of human- and rat-derived receptors were equivalent (12.5 and 11.4 microM). Kact values for Mn were comparable in both human- and rat-derived adipocyte receptors. In addition to the functional differences between species, the apparent mol wt of the beta-subunit of rat-derived receptors (96,000) was consistently greater than that of human-derived receptor beta-subunits (93,000). In contrast to these in vitro findings, the ability of insulin to stimulate receptor kinase activity in isolated adipocytes was rapid, with a maximal effect by seconds. This was comparable for both rat and human tissues, suggesting that the in vitro autophosphorylation differences may not govern kinase activity in vivo.

    Title Postprandial Metabolic Responses to the Influence of Food Form.
    Date October 1988
    Journal The American Journal of Clinical Nutrition
    Excerpt

    To determine whether differences in the metabolic response to two common starches could be eliminated by altering the physical form of food, 12 normal and 6 noninsulin-dependent diabetic (NIDDM) subjects were studied after consumption of test loads of whole and blended rice and potato. In normal and NIDDM subjects the lower postprandial glycemia and insulinemia of whole rice was eliminated and became similar to that of whole potato, which was unaffected by blending. The glucagon responses were unchanged and similar in both groups under all study conditions. In both normal and NIDDM subjects the glucose and insulin response to a particular starch is not a stable feature dependent on the unique characteristics of the starch molecule but is affected by food processing and the form in which it is presented to the gastrointestinal tract.

    Title Restriction-fragment-length Polymorphism in Insulin-receptor Gene and Insulin Resistance in Niddm.
    Date August 1988
    Journal Diabetes
    Excerpt

    Restriction-enzyme analysis of genomic DNA from 52 White and Hispanic nondiabetic subjects and 51 subjects with non-insulin-dependent diabetes (NIDDM) was carried out with insulin-receptor cDNA probes. A polymorphic 5.8-kilobase SstI fragment was found in 12 (23.5%) of 51 NIDDM subjects but only in 4 (7.7%) of 52 nondiabetic control subjects. This association is significant by chi 2-analysis (P less than .05). Furthermore, the nondiabetic subjects with the polymorphism were found to have hyperinsulinemia and/or nondiagnostic glucose tolerance. The polymorphism is a genetic marker for a phenotype that is neither necessary nor, by itself, sufficient for NIDDM. Nevertheless, it may indicate that insulin resistance functionally related to an insulin-receptor gene polymorphism is the proximal cause of NIDDM in at least one subset of the population.

    Title Secretion and Hepatic Extraction of Insulin After Weight Loss in Obese Noninsulin-dependent Diabetes Mellitus.
    Date June 1988
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    We assessed the effects of weight loss on pancreatic secretion and hepatic extraction of insulin in 11 obese subjects with noninsulin-dependent diabetes mellitus. Weight loss of 15.4 +/- 2.0 kg (mean +/- SE) resulted in decreased fasting insulin [20.2 +/- 2.5 to 9.8 +/- 2.5 microU/mL (145 +/- 18 to 70 +/- 18 pmol/L); P less than 0.02] and C-peptide (850 +/- 80 to 630 +/- 110 pmol/L; P less than 0.05) levels. The plasma glucose response to oral glucose and iv glucagon was improved with unchanged peripheral insulin levels. When plasma glucose levels were matched to those before weight loss, peripheral serum insulin and plasma C-peptide responses to iv glucagon were increased and similar to those in obese nondiabetic subjects studied at euglycemia. The total insulin response (area under the curve) to iv glucagon was reduced 30% (P less than 0.005), while the total C-peptide response area did not change after weight loss. At matched hyperglycemia, the total response area was enhanced 72% for insulin (P less than 0.002) and 64% for C-peptide (P less than 0.001). Incremental (above basal) response areas after weight loss did not change for insulin, but increased 66% for C-peptide (P less than 0.05). The incremental areas were augmented nearly 2-fold (196%) for insulin (P less than 0.01) and 1.7-fold (173%) for C-peptide (P less than 0.01) when assessed at matched hyperglycemia. Both basal (7.3 +/- 0.5 to 14.1 +/- 1.8; P less than 0.01) and total stimulated (6.1 +/- 0.4 to 8.8 +/- 1.4; P less than 0.05) C-peptide to insulin molar ratios increased after weight loss. We conclude that after weight loss in noninsulin-dependent diabetes mellitus, 1) insulin secretion is decreased in the basal state but increased after stimulation; 2) changes in insulin secretion are reflected by peripheral levels of C-peptide but not insulin, due in part to enhanced hepatic insulin extraction; and 3) at matched levels of hyperglycemia insulin secretion is markedly increased and similar to that in obese nondiabetic subjects studied at euglycemia.

    Title The Effects of Biosynthetic Human Proinsulin on Carbohydrate Metabolism in Non-insulin-dependent Diabetes Mellitus.
    Date March 1987
    Journal The New England Journal of Medicine
    Excerpt

    We compared the glucose-lowering effect of proinsulin, the precursor molecule of insulin, with that of insulin itself. In patients with non-insulin-dependent diabetes mellitus (NIDDM) in whom proinsulin (0.2 U per kilogram of body weight) was subcutaneously injected at 9 a.m., fasting glucose levels (247 +/- 22 mg per deciliter [+/- SEM]) became normal within six hours and elevated rates of hepatic glucose output were lowered. The response to regular insulin (0.2 U per kilogram) was of similar magnitude but faster. Glucose clearance was stimulated less by proinsulin, reflecting its preferential action in suppressing glucose output. Hypoglycemia occurred in five of nine insulin-treated patients, but in only one of nine proinsulin-treated patients. After proinsulin injection at bedtime (30.5 +/- 4 U), serum proinsulin concentrations reached a peak by five hours and declined gradually thereafter. Fasting hepatic glucose output became normal, and euglycemia was sustained without overnight hypoglycemia. Proinsulin reduced plasma glucose more effectively than an equal unit dosage of NPH insulin, but since higher doses of NPH insulin were not used, no conclusions could be drawn about the relative desirability of these preparations for clinical use. We conclude that subcutaneously injected proinsulin has prolonged pharmacokinetics in plasma and can normalize plasma glucose in NIDDM characterized by severe hyperglycemia; as compared with the hypoglycemic effects of regular insulin, those of proinsulin are mostly due to suppression of hepatic glucose output, with little stimulation of glucose disposal and less hypoglycemia; and proinsulin may have a role in the treatment of NIDDM.

    Title Decreased Kinase Activity of Insulin Receptors from Adipocytes of Non-insulin-dependent Diabetic Subjects.
    Date January 1987
    Journal The Journal of Clinical Investigation
    Excerpt

    The tyrosine kinase activity of the insulin receptor was examined with partially-purified insulin receptors from adipocytes obtained from 13 lean nondiabetics, 14 obese nondiabetics, and 13 obese subjects with non-insulin-dependent diabetes (NIDDM). Incubation of receptors at 4 degrees C with [gamma-32P]ATP and insulin resulted in a maximal 10-12-fold increase in autophosphorylation of the 92-kDa beta-subunit of the receptor with a half maximal effect at 1-3 ng/ml free insulin. Insulin receptor kinase activity in the three experimental groups was measured by means of both autophosphorylation and phosphorylation of the exogenous substrate Glu4:Tyr1. In the absence of insulin, autophosphorylation and Glu4:Tyr1 phosphorylation activities, measured with equal numbers of insulin receptors, were comparable among the three groups. In contrast, insulin-stimulated kinase activity was comparable in the control and obese subjects, but was reduced by approximately 50% in the NIDDM group. These findings indicate that the decrease in kinase activity in NIDDM resulted from a reduction in coupling efficiency between insulin binding and activation of the receptor kinase. The insulin receptor kinase defects observed in NIDDM could be etiologically related to insulin resistance in NIDDM and the pathogenesis of the diabetic state.

    Title Effects of Weight Loss on Mechanisms of Hyperglycemia in Obese Non-insulin-dependent Diabetes Mellitus.
    Date October 1986
    Journal Diabetes
    Excerpt

    To quantitate the effects of weight loss on the mechanisms responsible for hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM), eight obese subjects with NIDDM were studied before and after weight reduction with posttreatment assessment after 3 wks of isocaloric (weight maintenance) refeeding. After weight loss of 16.8 +/- 2.7 kg (mean +/- SE), the fasting plasma glucose level decreased 55% from 277 +/- 21 to 123 +/- 8 mg/dl. The individual fasting glucose levels were highly correlated with the elevated basal rates of hepatic glucose output (HGO) (r = 0.91, P less than .001), which fell from 138 +/- 11 to 87 +/- 5 mg X m-2 X min-1 after weight loss. The change in fasting plasma glucose also correlated significantly with the change in the basal rates of HGO (r = 0.74, P less than .05). This was associated with reduced fasting serum levels of glucagon (from 229 +/- 15 to 141 +/- 12 pg/ml), reduced free fatty acids (from 791 +/- 87 to 379 +/- 35 mu eq/L), and unchanged basal insulin levels (17 +/- 4 to 15 +/- 2 microU/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Handedness Patterns in Autism Suggest Subtypes.
    Date July 1986
    Journal Journal of Autism and Developmental Disorders
    Excerpt

    The present study reports preliminary data from two unselected samples of carefully diagnosed autistic subjects (children and adults) and an assessment procedure that includes a large sample of items, appropriate for lower-functioning autistic subjects, with multiple presentations within and between sessions 1 week apart. The study seeks to determine (1) whether a raised incidence of non-right-handedness exists in these samples (2) if so, what constructs best represent this shift in the handedness distribution (i.e., phenotype and CNS substrate) and (3) whether these handedness phenotypes are associated with different levels of cognitive functioning. The results reveal a dramatic shift away from right-handedness in both autistic samples, due to a raised incidence of two phenotypes, manifest left-handedness and ambiguous handedness. The ambiguously handed, who were postulated to represent substantial bilateral CNS pathology due to early brain injury, were found to have much lower intellectual scores in one of the study samples.

    Title Metabolic Consequence of Two-week Fructose Feeding in Diabetic Subjects.
    Date June 1986
    Journal Diabetes Care
    Excerpt

    We studied the metabolic effects of 2-wk fructose feeding as the sweetener in the diet of seven non-insulin-dependent diabetic individuals. The data demonstrated reduced postprandial hyperglycemia to an oral glucose challenge after 14 days without a significant difference in insulin response. There was no change in the markedly blunted glucose response to a fructose challenge but a significantly lower insulin response (area under the 3-h curve) was observed after 14 days of fructose feeding. There was reduced postprandial hyperglycemia after 14 days of fructose feeding with test meals as compared with baseline, without significant differences in insulin response. We also found no significant difference in free fatty acids, cholesterol, high-density lipoprotein (HDL) cholesterol, pyruvate, lactate, or uric acid after fructose feedings. There was a 13% increase in triglyceride levels after 14 days in 5 subjects with initial fasting hypertriglyceridemia (greater than 150 mg/dl). Insulin receptor binding to isolated adipocytes did not change after 14 days of fructose feeding.

    Title Metabolic Consequences of Very-low-calorie Diet Therapy in Obese Non-insulin-dependent Diabetic and Nondiabetic Subjects.
    Date March 1986
    Journal Diabetes
    Excerpt

    To determine the effects of very-low-calorie diets on the metabolic abnormalities of diabetes and obesity, we have studied 10 obese, non-insulin-dependent diabetic (NIDDM) and 5 obese, nondiabetic subjects for 36 days on a metabolic ward during consumption of a liquid diet of 300 kcal/day with 30 g of protein. Rapid improvement occurred in the glycemic indices of the diabetic subjects, with mean (+/- SEM) fasting plasma glucose falling from 291 +/- 21 to 95 +/- 6 mg/dl (P less than 0.001) and total glycosylated hemoglobin from 13.1 +/- 0.7% to 8.8 +/- 0.3% (P less than 0.001) (normal reference range 5.5-8.5%). Lipid elevations were normalized with plasma triglycerides reduced to less than 100 mg/dl and total plasma cholesterol to less than 150 mg/dl in both groups. Hormonal and substrate responses were also comparable between groups with reductions in insulin and triiodothyronine and moderate elevations in blood and urinary ketoacid levels without a corresponding rise in free fatty acids. Electrolyte balance for sodium, potassium, calcium, and phosphorus was initially negative but approached equilibrium by completion of the study. Magnesium, in contrast, remained in positive balance in both groups throughout. Total nitrogen loss varied widely among all subjects, ranging from 70 to 367 g, and showed a strong positive correlation with initial lean body mass (N = 0.83, P less than 0.001) and total weight loss (N = 0.87, P less than 0.001). The nondiabetic group, which had a significantly greater initial body weight and lean body mass than the diabetic group, also had a significantly greater weight loss of 450 +/- 31 g/day compared with 308 +/- 19 g/day (P less than 0.01) in the diabetic subjects. The composition of the weight lost at completion was similar in both groups and ranged from 21.6% to 31.3% water, 3.9% to 7.8% protein, and 60.9% to 74.5% fat. The contribution of both water and protein progressively decreased and fat increased, resulting in unchanged caloric requirements during the diet. This study demonstrates that short-term treatment with a very-low-calorie diet in both obese diabetic and nondiabetic subjects results in: safe and effective weight loss associated with the normalization of elevated glucose and lipid levels, a large individual variability in total nitrogen loss determined principally by the initial lean body mass, and progressive increments in the contribution of fat to weight loss with stable caloric requirements and no evidence of a hypometabolic response.

    Title Glycemic Effects of Intensive Caloric Restriction and Isocaloric Refeeding in Noninsulin-dependent Diabetes Mellitus.
    Date November 1985
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    To assess the effects of very low caloric (VLC) diets on glucose homeostasis in noninsulin-dependent diabetes mellitus, 30 obese subjects with NIDDM were studied for 40 days while eating a 330 Cal/day diet, with a subgroup of 12 subjects further evaluated during 40 days of refeeding. All subjects successfully lost weight, with an average weight loss of 4.6 +/- 0.2 kg (+/- SEM) after 10 days, 7.1 +/- 0.3 kg after 20 days, and 10.5 +/- 0.4 kg after 40 days of VLC diet therapy. Thus, weight loss was steady and progressive throughout the diet period. In contrast, the majority (87%) of the reduction in mean fasting plasma glucose (FPG) levels (297 +/- 13 to 158 +/- 10 mg/dl; P less than 0.001) occurred after 10 days of VLC diet therapy, with a further reduction in glucose levels to 138 +/- 9 mg/dl on day 40. The FPG response measured after 10 days of VLC diet was unrelated to the degree of obesity, rate or extent of weight loss, or prevailing insulin levels, but did correlate significantly with the initial FPG level (r = 0.37; P less than 0.05) and duration of diabetes (r = 0.42; P less than 0.05). After discontinuation of the VLC diet and refeeding of an isocaloric (weight maintenance) diet in 12 subjects, a variable increase in the FPG occurred, with an average increase of 80% after 40 days of refeeding. However, the mean FPG level after 40 days of refeeding was still markedly lower than that before VLC diet therapy (254 +/- 20 vs. 167 +/- 14 mg/dl; P less than 0.02) despite withdrawal of antidiabetic medication in all subjects. The basal hepatic glucose output (HGO) fell rapidly from 149 +/- 13 to 81 +/- 5 mg/M2 X min (P less than 0.001) after 10 days of VLC diet and rose from 67 +/- 4 to 88 +/- 7 mg/M2 X min (P less than 0.001) after 10 days of refeeding. Basal HGO demonstrated a highly significant positive correlation with FPG levels (r = 0.89; P less than 0.001) before and during both VLC diet therapy and refeeding. A significant correlation was also found between the change in FPG level and the change in basal HGO (r = 0.84; P less than 0.001) during both VLC diet and refeeding. Compared to that before the VLC diet, glucose tolerance to mixed meals was markedly improved during the refeeding period, with no change in circulating insulin levels.(ABSTRACT TRUNCATED AT 400 WORDS)

    Title Insulin Resistance in Non-insulin Dependent (type Ii) and Insulin Dependent (type I) Diabetes Mellitus.
    Date October 1985
    Journal Advances in Experimental Medicine and Biology
    Excerpt

    Insulin resistance is a characteristic feature of non-insulin dependent diabetes mellitus (NIDDM) due to target tissue defects in insulin action. Abnormalities of cellular insulin action can be divided into receptor and post-receptor defects. Patients with impaired glucose tolerance are insulin resistant due to decreased insulin receptors resulting in decreased insulin sensitivity and rightward shifted in vivo dose response curves. Patients with NIDDM are insulin resistant due to a combination of receptor and post-receptor defects. The greater the severity of the diabetes (greater fasting hyperglycemia) the greater the post-receptor defect, and in those patients with more significant fasting hyperglycemia the post-receptor defect is the predominant abnormality leading to the insulin resistant state. At least one of the abnormalities underlying this post-receptor defect involves a decrease in glucose transport system activity in freshly isolated adipocytes. This defect in glucose transport, is not expressed in cultured fibro-blasts, indicating that the abnormality in glucose disposal seen in vivo and in glucose transport seen in freshly isolated cells is an acquired phenomenon. Consistent with this, the post-receptor defect is partially reversible by insulin therapy, which leads to a 50-70% reversal of the reduced rates of in vivo glucose disposal and in vitro glucose transport. Insulin resistance also exists in poorly controlled IDDM patients, due to a postreceptor defect in insulin action. This insulin resistance is not present in well controlled IDDM patients, and is completely reversible when poorly controlled patients are treated with intensive insulin therapy. Insulin is produced in the pancreatic beta cell as the primary biosynthetic product preproinsulin. This peptide is rapidly converted to proinsulin (MW approximately 9000). Proinsulin is converted to insulin (MW approximately 6000) plus C-peptide in the secretory granule with a small amount (approximately 5 percent) of the proinsulin remaining unconverted. After a brief time in the peripheral circulation (half-life six to 10 minutes), insulin interacts with target tissues to exert its biologic effects. One of insulin's major biologic effects is the promotion of overall glucose metabolism, and abnormalities of this aspect of insulin action can lead to a number of important clinical and pathophysiologic states including Type II diabetes, also known as non-insulin-dependent diabetes mellitus (NIDDM). Since insulin travels from the beta cell through the circulation to the target tissues, abnormalities at any of these loci can influence the ultimate action of the hormone. These abnormalities, all

    Title Protocol for the National Cooperative Dialysis Study.
    Date August 1983
    Journal Kidney International. Supplement
    Title Assessment of Nutritional Status of the National Cooperative Dialysis Study Population.
    Date August 1983
    Journal Kidney International. Supplement
    Title In Vitro Macrophage Antimicrobial Activities and in Vivo Susceptibility to Leishmania Tropica Infection.
    Date August 1983
    Journal Advances in Experimental Medicine and Biology
    Title Susceptibility of Inbred Mice to Leishmania Tropica Infection: Correlation of Susceptibility with in Vitro Defective Macrophage Microbicidal Activities.
    Date July 1983
    Journal Cellular Immunology
    Excerpt

    Eleven mouse strains were inoculated in footpads with amastigotes of Leishmania tropica and observed for 12 weeks. Liver and spleen impression smears from infected mice were examined for the presence of intracellular parasites. Four strains (BALB/cJ, C57L/J, NZW/N, and P/J) failed to heal the subcutaneous lesion and showed evidence of systemic infection; the remaining seven strains (A/J, C3H/HeJ, C3H/HeN, C3HeB/FeJ, C57BL/6J, C57BL/10J, and C57BL/10ScN) were each resistant to infection and resolved their lesions by Week 10. Macrophages from the four susceptible strains could not be activated to kill L. tropica amastigotes by treatment with soluble lymphocyte products in vitro. In contrast, macrophages from all seven resistant strains responded to lymphokine treatment and eliminated 80-90% of intracellular parasites. These results suggest that in vitro macrophage microbicidal activities predict the course of systemic leishmanial disease.

    Title Hypothyroidism, Triiodothyronine Antibodies, and Hyperprolactinemia.
    Date July 1981
    Journal Archives of Internal Medicine
    Excerpt

    This report describes the development of triiodothyronine (T3) antibodies in a patient with Hashimoto's thyroiditis that resulted in compensated hypothyroidism and hyperprolactinemia. The patient, a 23-year-old woman, had a small goiter, modest elevation of thyrotropin (TSH) and prolactin (PRL) levels, and a markedly elevated T3 level. Circulating antibodies to T3 were demonstrated that presumably rendered the T3 physiologically inactive. Saturation of antibody binding sites by incremental dosages of liothyronine (triiodothyronine) sodium (12.5 to 87.5 microgram/day) resulted in normalization of both the TSH and PRL levels.

    Title Mass Balance: a Quantitative Guide to Clinical Nutritional Therapy. Ii. The Dialyzed Patient.
    Date January 1980
    Journal Journal of the American Dietetic Association
    Excerpt

    The concepts of mass balance are extended to the nutritional management of the patient with chronic renal failure on dialysis. The use of these concepts permits estimation of protein catabolism from calculated rates of urea generation, using measurement of blood urea levels. Protein catabolic rate will equal intake in the stable patient (zero nitrogen balance), allowing for accurate nutritional screening in a large dialysis population for whom these values are available without individual dietary surveys. This has resulted in a four-fold reduction in routine monitoring of protein nutrition in such patients, freeing the dietitian to concentrate on specific problems. These concepts also comprise a key aspect of the National Cooperative Dialysis Study which seeks to maintain BUN at different levels in four carefully controlled modes of dialysis therapy. With these methods, the monitoring and control of BUN and protein intake has made the dietitian a pivotal member of this study staff.

    Title Rotavirus Infection in Commercial Laying Hens.
    Date June 1979
    Journal The Veterinary Record
    Title Implications of Acquired Changes in Tolerance for the Treatment of Alcohol Problems.
    Date July 1978
    Journal Addictive Behaviors
    Title Is Adiposopathy (sick Fat) an Endocrine Disease?
    Date
    Journal International Journal of Clinical Practice
    Excerpt

    OBJECTIVE: To review current consensus and controversy regarding whether obesity is a 'disease', examine the pathogenic potential of adipose tissue to promote metabolic disease and explore the merits of 'adiposopathy' and 'sick fat' as scientifically and clinically useful terms in defining when excessive body fat may represent a 'disease'. METHODS: A group of clinicians and researchers, all with a background in endocrinology, assembled to evaluate the medical literature, as it pertains to the pathologic and pathogenic potential of adipose tissue, with an emphasis on metabolic diseases that are often promoted by excessive body weight. RESULTS: The data support pathogenic adipose tissue as a disease. Challenges exist to convince many clinicians, patients, healthcare entities and the public that excessive body fat is often no less a 'disease' than the pathophysiological consequences related to anatomical abnormalities of other body tissues. 'Adiposopathy' has the potential to scientifically define adipose tissue anatomic and physiologic abnormalities, and their adverse consequences to patient health. Adiposopathy acknowledges that when positive caloric balance leads to adipocyte hypertrophy and visceral adiposity, then this may lead to pathogenic adipose tissue metabolic and immune responses that promote metabolic disease. From a patient perspective, explaining how excessive caloric intake might cause fat to become 'sick' also helps provide a rationale for patients to avoid weight gain. Adiposopathy also better justifies recommendations of weight loss as an effective therapeutic modality to improve metabolic disease in overweight and obese patients. CONCLUSION: Adiposopathy (sick fat) is an endocrine disease.

    Title Sedentary Aging Increases Resting and Exercise-induced Intramuscular Free Radical Formation.
    Date
    Journal Journal of Applied Physiology (bethesda, Md. : 1985)
    Excerpt

    Mitochondrial free radical formation has been implicated as a potential mechanism underlying degenerative senescence, although human data are lacking. Therefore, the present study was designed to examine if resting and exercise-induced intramuscular free radical-mediated lipid peroxidation is indeed increased across the spectrum of sedentary aging. Biopsies were obtained from the vastus lateralis in six young (26 + or - 6 yr) and six aged (71 + or - 6 yr) sedentary males at rest and after maximal knee extensor exercise. Aged tissue exhibited greater (P < 0.05 vs. the young group) electron paramagnetic resonance signal intensity of the mitochondrial ubisemiquinone radical both at rest (+138 + or - 62%) and during exercise (+143 + or - 40%), and this was further complemented by a greater increase in alpha-phenyl-tert-butylnitrone adducts identified as a combination of lipid-derived alkoxyl-alkyl radicals (+295 + or - 96% and +298 + or - 120%). Lipid hydroperoxides were also elevated at rest (0.190 + or - 0.169 vs. 0.148 + or - 0.071 nmol/mg total protein) and during exercise (0.567 + or - 0.259 vs. 0.320 + or - 0.263 nmol/mg total protein) despite a more marked depletion of ascorbate and uptake of alpha/beta-carotene, retinol, and lycopene (P < 0.05 vs. the young group). The impact of senescence was especially apparent when oxidative stress biomarkers were expressed relative to the age-related decline in mitochondrial volume density and absolute power output at maximal exercise. In conclusion, these findings confirm that intramuscular free radical-mediated lipid peroxidation is elevated at rest and during acute exercise in aged humans.

    Title Folate Pathway and Nonsyndromic Cleft Lip and Palate.
    Date
    Journal Birth Defects Research. Part A, Clinical and Molecular Teratology
    Excerpt

    BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common complex birth defect. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs), C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. Here, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP, and were there detectable interactions between these genes and environmental exposures? METHODS: Fourteen folate metabolism-related genes were interrogated using 89 SNPs in multiplex and simplex non-Hispanic white and Hispanic NSCLP families. RESULTS: Evidence for a risk association between NSCLP and SNPs in NOS3 and TYMS was detected in the non-Hispanic white group, whereas associations with MTR, BHMT2, MTHFS, and SLC19A1 were detected in the Hispanic group. Evidence for over-transmission of haplotypes and gene interactions in the methionine arm was detected. CONCLUSIONS: These results suggest that perturbations of the genes in the folate pathway may contribute to NSCLP. There was evidence for an interaction between several SNPs and maternal smoking, and for one SNP with gender of the offspring. These results provide support for other studies that suggest that high maternal homocysteine levels may contribute to NSCLP and should be further investigated. Birth Defects Research (Part A), 2010. © 2010 Wiley-Liss, Inc.

    Title In Vivo Activation of Rock1 by Insulin is Impaired in Skeletal Muscle of Humans with Type 2 Diabetes.
    Date
    Journal American Journal of Physiology. Endocrinology and Metabolism
    Excerpt

    To determine whether the serine/threonine Rho-kinase (ROCK) 1 is activated by insulin in vivo in humans and whether impaired activation of ROCK1 could play a role in the pathogenesis of insulin resistance, we measured the activity of ROCK1 and the protein content of Rho family in vastus lateralis muscle of lean, obese nondiabetic and obese type 2 diabetic subjects. Biopsies were taken after an overnight fast and after a 3 hr hyperinsulinemic-euglycemic clamp. Insulin-stimulated glucose disposal rate (GDR) was reduced 38% in obese nondiabetic subjects compared to lean, 62% in obese diabetic subjects compared to lean and 39% in obese diabetic compared to obese nondiabetic subjects (all comparisons p<0.001). Insulin-stimulated IRS-1 tyrosine phosphorylation is impaired 41-48% in diabetic subjects compared with lean or obese subjects. Basal activity of ROCK1 was similar in all groups. Insulin increased ROCK1 activity 2.1-fold in lean and 1.7-fold in obese nondiabetic subjects in muscle. However, ROCK1 activity did not increase in response to insulin in muscle of obese type 2 diabetic subjects without change in ROCK1 protein levels. Importantly, insulin-stimulated ROCK1 activity was positively correlated with insulin-mediated GDR in lean subjects (p<0.01), but not in obese or type 2 diabetic subjects. Moreover, RhoE GTPase that inhibits the catalytic activity of ROCK1 by binding to the kinase domain of the enzyme is notably increased in obese type 2 diabetic subjects, accounting for defective ROCK1 activity. Thus, these data suggest that ROCK1 plays an important role in the pathogenesis of resistance to insulin action on glucose disposal in muscle of obese type 2 diabetic subjects.

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