S Mudaliar

VA San Diego Healthcare System, San Diego, California, United States

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Publications (30)200.32 Total impact

  • Diabetes 10/2013; 62(11):3920-3926. DOI:10.2337/db13-0265 · 8.47 Impact Factor
  • S Mudaliar
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    ABSTRACT: The progressive deterioration of glycaemic control in individuals with type 2 diabetes mellitus (T2DM) results from insulin resistance combined with the ongoing loss of β-cell function. Although it had been suggested that most β-cell dysfunction occurs after the development of T2DM, studies have documented a substantial early loss of β-cell function, particularly during the prediabetic state. In patients diagnosed with T2DM, β-cell function continues to decline despite treatment with commonly prescribed antihyperglycaemic medications, and ultimately exogenous insulin administration is required to maintain optimal glycaemic control. Thus, interventions to address the early decline in β-cell function could potentially alter the course of T2DM, preventing or delaying its onset and decreasing the incidence of complications. Original research and review articles on this topic were identified in a PubMed search from January 2000 through August 2012. Data from prospective studies and clinical trials suggest that lifestyle modifications and certain antihyperglycaemic medications, including thiazolidinediones (TZDs), glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors and insulin, may preserve or enhance β-cell function. The implication of current data is that early initiation of lifestyle modifications and antihyperglycaemic agents that preserve β-cell function might reverse or delay progression to T2DM in those with prediabetes. Moreover, improved β-cell function may confer more durable glucose control and perhaps reduce/delay the incidence of diabetic complications. Long-term studies are needed to validate this hypothesis.
    International Journal of Clinical Practice 09/2013; 67(9):876-87. DOI:10.1111/ijcp.12154 · 2.54 Impact Factor
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    ABSTRACT: AIMS: This study examined effects of pioglitazone on body weight and bone mineral density prospectively in patients with impaired glucose tolerance since pioglitazone (TZD) increases body weight and body fat in diabetic patients and increases the risk of bone fractures. MATERIALS AND METHODS: A total of 71 men and 163 women aged 49.3 (10.7) years [mean (SD)]; BMI, 34.5 (5.9) kg/m(2) were recruited at 5 sites for measurements of body composition by dual energy x-ray absorptiometry at baseline and at conversion to diabetes or study end, if they had not converted. RESULTS: Mean follow-up was 33.6 months in the pioglitazone group and 32.1 months in the placebo group. Body weight increased 4.63±0.60 (m±SE) kg in the pioglitazone group compared to 0.98±0.62 kg in the PIO group (p <0.0001). Body fat rose 4.89±0.42 kg in the pioglitazone group compared to 1.41±0.44 kg, p <0.0001) in placebo-treated subjects. The increase in fat was greater in legs and trunk than in the arms. Bone mineral density (BMD) was higher in all regions in men and significantly so in most. PIO decreased BMD significantly in the pelvis in men and women, decreased BMD in the thoracic spine and ribs of women and the lumbar spine and legs of men. Bone mineral content also decreased significantly in arms, legs, trunk, and in the total body. CONCLUSIONS: Pioglitazone increased peripheral fat more than truncal fat and decreased bone mineral density in several regions of the body.
    Diabetes Obesity and Metabolism 04/2013; DOI:10.1111/dom.12099 · 5.18 Impact Factor
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    S Mudaliar, R R Henry
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    ABSTRACT: The incretins are gut hormones secreted in response to nutrient/carbohydrate ingestion and act on the pancreatic beta cell to amplify glucose-stimulated insulin secretion. Incretin hormone-based treatments for patients with type 2 diabetes represent a major advance in diabetes therapeutics. The ability of the incretin agents (glucagon-like peptide 1 [GLP-1] agonists and dipeptidyl peptidase IV [DPP-4] inhibitors) to improve glycaemia with a low associated risk of hypoglycaemia, together with beneficial/neutral effects on body weight, offers a significant advantage for both patients and treating clinicians. In this edition of 'Then and Now,' it is useful to look back 25 years and reflect upon the developments in this field since Nauck and colleagues published two seminal papers. In 1986 they first documented a reduced incretin effect in patients with type 2 diabetes (Diabetologia 29:46-52), and then in 1993 they demonstrated that, in patients with poorly controlled type 2 diabetes, a single exogenous infusion of an incretin (GLP-1) increased insulin levels in a glucose-dependent manner and normalised fasting hyperglycaemia (Diabetologia 36:741-744). In the ensuing 26 years, progress in the field of incretin hormones has resulted in a greater understanding of the relative roles of GLP-1 and glucose-dependent insulinotropic polypeptide secretion and activity in the pathogenesis of type 2 diabetes and the important recognition that native GLP-1 is quickly degraded by the ubiquitous protease DPP-4. This has led to the development of GLP-1 agonists that are resistant to degradation by DPP-4 and of selective inhibitors of DPP-4 activity as therapeutic agents. GLP-1 agonists (exenatide and liraglutide) and DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin and linagliptin) currently represent effective treatment options for patients with type 2 diabetes. Several additional agents are in the pipeline, including longer acting DPP-4-resistant GLP-1 agonists. More exciting, however, is the increasing recognition that the incretin agents have numerous extra-glycaemic effects that could translate into potential cardiovascular and other benefits.
    Diabetologia 05/2012; 55(7):1865-8. DOI:10.1007/s00125-012-2561-x · 6.88 Impact Factor
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    ABSTRACT: Colesevelam lowers glucose and low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus. This study examined the mechanisms by which colesevelam might affect glucose control. In this 12-week, randomized, double-blind, placebo-controlled study, subjects with type 2 diabetes and haemoglobin A(1c) (HbA(1c)) ≥7.5% on either stable diet and exercise or sulphonylurea therapy were randomized to colesevelam 3.75 g/day (n = 16) or placebo (n = 14). Hepatic/peripheral insulin sensitivity was evaluated at baseline and at week 12 by infusion of (3) H-labelled glucose followed by a 2-step hyperinsulinemic-euglycemic clamp. Two 75-g oral glucose tolerance tests (OGTTs) were conducted at baseline, one with and one without co-administration of colesevelam. A final OGTT was conducted at week 12. HbA(1c) and fasting plasma glucose (FPG) levels were evaluated pre- and post-treatment. Treatment with colesevelam, compared to placebo, had no significant effects on basal endogenous glucose output, response to insulin or on maximal steady-state glucose disposal rate. At baseline, co-administration of colesevelam with oral glucose reduced total area under the glucose curve (AUC(g)) but not incremental AUC(g). At week 12, neither total AUC(g) nor incremental AUC(g) were changed from pre-treatment values in either group. Post-load insulin levels increased with colesevelam at 30 and 120 min, but these changes in total area under the insulin curve (AUC(i)) and incremental AUC(i) did not differ between groups. Both HbA(1c) and FPG improved with colesevelam, but treatment differences were not significant. Colesevelam does not affect hepatic or peripheral insulin sensitivity and does not directly affect glucose absorption.
    Diabetes Obesity and Metabolism 08/2011; 14(1):40-6. DOI:10.1111/j.1463-1326.2011.01486.x · 5.18 Impact Factor
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    ABSTRACT: To evaluate the effects of intensive insulin therapy alone and with added pioglitazone on body weight, fat distribution, lean body mass (LBM) and liver fat in type 2 diabetic patients. Twenty-five insulin-treated, obese patients with type 2 diabetes were randomized to addition of pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12-16 weeks. Dual-energy X-ray absorptiometry/abdominal computed tomography scans were performed before/after treatment. LBM, visceral/subcutaneous adipose tissue (VAT/SAT) and liver/spleen (L/S) attenuation ratios were measured pre-/posttreatment (a ratio <1 represents fatty liver). Intensive insulin alone and insulin + pioglitazone significantly improved glycaemic control (7.8 ± 0.3 to 7.2 ± 0.3% and 7.6 ± 0.3 to 7.1 ± 0.4%, respectively). Body weight gain was greater with insulin + pioglitazone (4.9 ± 4.5 kg) versus insulin therapy alone (1.7 ± 0.7 kg). SAT increased significantly with pioglitazone + insulin therapy (393.9 ± 48.5 to 443.2 ± 56.7 cm(2) , p < 0.01) compared to a non-significant increase with insulin therapy alone (412.9 ± 42.5 to 420.8 ± 43.8 cm(2) ). VAT decreased non-significantly in both groups (240.3 ± 41.7 to 223.8 ± 38.1 cm(2) with insulin + pioglitazone and 266.6 ± 27.4 to 250.5 ± 22.2 cm(2) with insulin therapy). LBM increased significantly by 1.92 ± 0.74 kg with insulin + pioglitazone treatment. The L/S attenuation ratio in the placebo + insulin group decreased from 1.08 ± 0.1 to 1.04 ± 0.1 (p = ns) and increased from 1.00 ± 0.1 to 1.08 ± 0.05 (p = 0.06) in the pioglitazone + insulin group. Intensification of insulin therapy in type 2 diabetic patients causes modest weight gain and no change in body fat distribution, LBM or liver fat. In contrast, the addition of pioglitazone, at equivalent glycaemia, increases weight gain, fat mass and SAT; increases LBM and tends to decrease liver fat. These changes in fat distribution may contribute to the beneficial effects of pioglitazone, despite greater weight gain.
    Diabetes Obesity and Metabolism 06/2011; 13(6):505-10. DOI:10.1111/j.1463-1326.2011.01370.x · 5.18 Impact Factor
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    ABSTRACT: To study the effect of dipeptidyl peptidase-4 (DPP-4) inhibition with saxagliptin on β-cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. Patients in this randomized, parallel-group, double-blind, placebo-controlled study were drug-naïve, aged 43-69 years, with baseline haemoglobin A1c (HbA1c) 5.9-8.1%. Twenty patients received saxagliptin 5 mg once daily; 16 received placebo. Patients were assessed at baseline and week 12 by intravenous hyperglycaemic clamp (0-180 min, fasting state), and intravenous-oral hyperglycaemic clamp (180-480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C-peptide deconvolution. After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. In the fasting state, saxagliptin significantly increased insulin secretion by a 27.9% adjusted difference versus placebo (p = 0.02). Saxagliptin also improved glucagon area under the curve in the postprandial state (adjusted difference -21.8% vs. placebo, p = 0.03). DPP-4 inhibition with saxagliptin improves pancreatic β-cell function in postprandial and fasting states, and decreases postprandial glucagon concentration. Given the magnitude of enhancement of the insulin response in the fasting state, further study into the effect of DPP-4 inhibition on the β-cell is warranted.
    Diabetes Obesity and Metabolism 05/2011; 13(9):850-8. DOI:10.1111/j.1463-1326.2011.01417.x · 5.18 Impact Factor
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    ABSTRACT: To assess changes in insulin sensitivity in non-diabetic adults with schizophrenia or schizoaffective disorder treated with olanzapine or risperidone. One hundred and thirty patients were randomly assigned to 12 weeks double-blind treatment with olanzapine or risperidone. Insulin sensitivity was measured using a two-step euglycaemic, hyperinsulinaemic clamp procedure. Whole-body adiposity was measured using dual-energy X-ray absorptiometry. The primary endpoint was the within-group change from baseline in insulin sensitivity normalized to fat-free mass (M(ffm) /I) during the clamp procedure's low-insulin phase, using an analysis of covariance model including the covariate weight change. Forty-one olanzapine-treated and 33 risperidone-treated patients completed baseline and endpoint clamp measurements. Mean M(ffm) /I during the low-insulin phase declined 9.0% (p = 0.226) in olanzapine-treated patients and 13.2% (p = 0.047) in risperidone-treated patients (between-group difference p = 0.354). During the high-insulin phase, M(ffm) /I declined 10.4% (p = 0.036) in olanzapine-treated patients and 2.1% (p = 0.698) in risperidone-treated patients (between-group difference p = 0.664). Changes in M(ffm) /I correlated inversely with changes in body weight and adiposity, which were generally higher in olanzapine-treated patients. Significant within-group increases in fasting glucose, but not haemoglobin A1c (HbA1c), were observed during olanzapine treatment. The fasting glucose change was not correlated with M(ffm) /I changes. Small, but statistically significant, decrements in insulin sensitivity were observed in olanzapine- and risperidone-treated patients at 1 of 2 insulin doses tested. Significant increases in fasting glucose and insulin and total fat mass were observed only in olanzapine-treated patients. Changes in insulin sensitivity correlated significantly with changes in weight or adiposity, but not with changes in glucose.
    Diabetes Obesity and Metabolism 03/2011; 13(8):726-35. DOI:10.1111/j.1463-1326.2011.01398.x · 5.18 Impact Factor
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    ABSTRACT: 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. In addition to the 602 IGT participants, 115 persons with normal glucose tolerance (NGT) and 50 with impaired fasting glucose (IFG) were identified during screening and included in this analysis. Insulin secretion and insulin sensitivity indices were derived from plasma glucose and insulin during an OGTT. The acute insulin response (AIR) (0-10 min) and insulin sensitivity (S(I)) were measured with the frequently sampled intravenous glucose tolerance test (FSIVGTT) in a subset of participants. At baseline, fasting plasma glucose, 2 h postprandial glucose (OGTT) and HbA(1c) were 5.8 +/- 0.02 mmol/l, 10.5 +/- 0.05 mmol/l and 5.5 +/- 0.04%, respectively, in participants with IGT. Participants with IGT were characterised by defects in early (DeltaI (0-30)/DeltaG (0-30) x Matsuda index, where DeltaI is change in insulin in the first 30 min and DeltaG is change in glucose in the first 30 min) and total (DeltaI(0-120)/DeltaG(0-120) x Matsuda index) insulin secretion and in insulin sensitivity (Matsuda index and S(I)). Participants with IGT in whom 2 h plasma glucose was 7.8-8.3 mmol/l had a 63% decrease in the insulin secretion/insulin resistance (disposition) index vs participants with NGT and this defect worsened progressively as 2 h plasma glucose rose to 8.9-9.94 mmol/l (by 73%) and 10.0-11.05 mmol/l (by 80%). The Matsuda insulin sensitivity index was reduced by 40% in IGT compared with NGT (p < 0.005). In multivariate analysis, beta cell function was the primary determinant of glucose AUC during OGTT, explaining 62% of the variance. Our results strongly suggest that progressive beta cell failure is the main determinant of progression of NGT to IGT.
    Diabetologia 12/2009; 53(3):435-45. DOI:10.1007/s00125-009-1614-2 · 6.88 Impact Factor
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    ABSTRACT: 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. A total of 25 insulin-treated, obese patients with type 2 diabetes were randomized to pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for 12-16 weeks to achieve equivalent glycaemic control. We measured total body water (TBW) and extracellular/intracellular fluid by bioimpedance analysis; plasma/RBC volume with I(131)albumin; sodium handling by fractional excretion of sodium/lithium (FeNa/FeLi) and other renal/hormonal parameters. Intensification of insulin therapy and the addition of pioglitazone significantly improved glycaemia (HbA1C 7.8-7.2% and 7.6-7.1%) and increased body weight (1.7 and 4.9 kg) respectively. TBW increased 1.7 l with insulin alone (65% intracellular) and 1.6 l with added pioglitazone (75% extracellular) (p = 0.06 and 0.09 respectively). Plasma volume increased 0.2 +/- 0.1 l with insulin alone (p = 0.05) and 0.4 +/- 0.1 l with added pioglitazone (p < 0.05). Extravascular, extracellular (interstitial) fluid increased significantly and more with added pioglitazone (0.8 +/- 0.2 l, p < 0.01) than with insulin alone (0.4 +/- 0.2 l, p = ns). At steady-state, FeLi (marker of proximal-tubular sodium delivery to the distal nephron) increased significantly with added pioglitazone (12.4 +/- 1.3 to 18.0 +/- 3.2%) vs. no significant change with insulin alone (15.4 +/- 1.2 to 14.5 +/- 2.3%). There were no significant changes in the other parameters. In intensively insulin-treated obese type 2 diabetic patients, at equivalent glycaemic control, the addition of pioglitazone causes greater weight gain, but a similar increase in body water that is mainly extracellular and interstitial compared with intracellular increase with insulin therapy alone. Pioglitazone also increases the filtered load of sodium reabsorbed at the distal nephron with no net change in FeNa.
    Diabetes Obesity and Metabolism 11/2009; 12(2):133-8. DOI:10.1111/j.1463-1326.2009.01126.x · 5.18 Impact Factor
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    ABSTRACT: 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.
    Molecular and Cellular Endocrinology 06/2009; 315(1-2):153-8. DOI:10.1016/j.mce.2009.05.020 · 4.24 Impact Factor
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    ABSTRACT: 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.
    Journal of Clinical Endocrinology &amp Metabolism 12/2001; 86(12):5838-47. DOI:10.1210/jc.86.12.5838 · 6.31 Impact Factor
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    ABSTRACT: 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.
    Journal of Clinical Endocrinology &amp Metabolism 10/2001; 86(9):4307-14. DOI:10.1210/jcem.86.9.7872 · 6.31 Impact Factor
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    ABSTRACT: 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.
    Metabolism 07/2001; 50(7):830-4. DOI:10.1053/meta.2001.24929 · 3.61 Impact Factor
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    ABSTRACT: 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. 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. 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. 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.
    Diabetologia 05/2001; 44(4):444-52. · 6.88 Impact Factor
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    ABSTRACT: Aims/hypothesis. To determine the independent and potentially synergistic effects of agonists for PPARγ 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 LG100 268 (4 μmol/l), an RXR agonist, or troglitazone (4.6 μmol/l), a PPARγ 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 LG100 268 and troglitazone, p < 0.01, respectively). The agent LG100 268 alone had little effect on the activity of glycogen synthase but the effect of troglitazone increased with LG100 268 (p p p 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 PPARγ protein expression, whereas LG100 268 had no effect. Furthermore, neither LG100 268 nor troglitazone had any effect on the protein expression of RXR isoforms or PPARα. Conclusion/interpretation. Co-activation of PPARγ and RXR results in additive or synergistic effects on glucose and lipid metabolism in skeletal muscle, but unlike troglitazone, LG100 268 does not alter expression of its own receptor. [Diabetologia (2001) 44: 444–452]
    Diabetologia 04/2001; 44(4):444-452. DOI:10.1007/s001250051642 · 6.88 Impact Factor
  • S Mudaliar, R R Henry
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    ABSTRACT: 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.
    Annual Review of Medicine 02/2001; 52:239-57. DOI:10.1146/annurev.med.52.1.239 · 15.48 Impact Factor
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    ABSTRACT: 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.
    Metabolism 08/2000; 49(8):962-8. DOI:10.1053/meta.2000.7717 · 3.61 Impact Factor
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    ABSTRACT: 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. 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. 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). 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.
    Diabetologia 03/2000; 43(3):304-11. DOI:10.1007/s001250050048 · 6.88 Impact Factor
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    ABSTRACT: 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.
    Diabetes 02/2000; 49(2):263-71. DOI:10.2337/diabetes.49.2.263 · 8.47 Impact Factor

Publication Stats

1k Citations
200.32 Total Impact Points

Institutions

  • 2000–2013
    • VA San Diego Healthcare System
      San Diego, California, United States
  • 1997–2011
    • University of California, San Diego
      • Department of Medicine
      San Diego, California, United States
  • 2001
    • National University (California)
      San Diego, California, United States
    • U.S. Department of Veterans Affairs
      Washington, Washington, D.C., United States