Enhancement of insulin-stimulated myocardial glucose uptake in patients with Type 2 diabetes treated with rosiglitazone. The Effect of a Thiazolidinedione Drug, Troglitazone, on Glycemia in Patients with Type 2 Diabetes Mellitus Poorly Controlled with Sulfonylurea and Metformin: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Effects of the dual peroxisome proliferator-activated receptor activator aleglitazar in patients with Type 2 Diabetes mellitus or prediabetes. Dual Peroxisome Proliferator–Activated Receptor α/δ Agonist GFT505 Improves Hepatic and Peripheral Insulin Sensitivity in Abdominally Obese Subjects Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Endothelial function and insulin resistance in polycystic ovary syndrome: the effects of medical therapy. Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. The peroxisome proliferator-activated receptor alpha agonist fenofibrate has no effect on insulin sensitivity compared to atorvastatin in type 2 diabetes mellitus; a randomised, double-blind controlled trial. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Effects of a novel selective peroxisome proliferator‐activated receptor‐α modulator, pemafibrate, on hepatic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance Effects of metformin and rosiglitazone treatment on insulin signaling and glucose uptake in patients with newly diagnosed type 2 diabetes: a randomized controlled study. Improved endothelial function with metformin in type 2 diabetes mellitus. The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice. Peroxisome Proliferator–Activated Receptor Ligand Bezafibrate for Prevention of Type 2 Diabetes Mellitus in Patients With Coronary Artery Disease A diabetes outcome progression trial (ADOPT): an international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients.
AIMS Peroxisome proliferator-activated receptor gamma ( PPARgamma ) activators have recently been identified as regulators of cellular proliferation , inflammatory responses and lipid and glucose metabolism . These agents prevent coronary arteriosclerosis and improve left ventricular remodelling and function in heart failure after myocardial infa rct ion . Improvement in myocardial metabolic state may be one of the mechanisms behind these findings . The aim of this study was to investigate the effects of rosiglitazone on myocardial glucose uptake in patients with Type 2 diabetes .  Placebo and metformin were used as control treatments . METHODS Forty-four patients were r and omized to treatment with rosiglitazone ( 4 mg b.i.d . ) , metformin ( 1 g b.i.d . ) or placebo in a 26-week double-blinded trial . Myocardial glucose uptake was measured using [(18)F]-2-fluoro-2-deoxy-D-glucose ( [(18)F]FDG ) and positron emission tomography ( PET ) during euglycaemic hyperinsulinaemia before and after the treatment . RESULTS Rosiglitazone increased insulin-stimulated myocardial glucose uptake by 38 % ( from 38.7 + /- 3.4 to 53.3 + /- 3.6 micromol 100 g(-1 ) min(-1 ) , P = 0.004 ) and whole body glucose uptake by 36 % ( P = 0.01 ) , while metformin treatment had no significant effect on myocardial ( 40.5 + /- 3.5 vs. 36.6 + /- 5.2 , NS ) or whole body glucose uptake . Myocardial work as determined by the rate-pressure-product was similar between the groups . Neither treatment had any significant effect on fasting serum free fatty acids ( FFA ) but the FFA levels during hyperinsulinaemia were more suppressed in the rosiglitazone group ( -47 % , P = 0.02 ) . Myocardial glucose uptake correlated inversely to FFA concentrations both before ( r = -0.54 , P = 0.002 ) and after ( r = -0.43 , P = 0.01 ) the treatment period in the pooled data . Furthermore , the increase in myocardial glucose uptake correlated inversely with interleukin-6 ( IL-6 ) concentrations ( r = -0.58 , P = 0.03 ) . CONCLUSIONS In addition to the improvement in whole body insulin sensitivity , rosiglitazone treatment enhances insulin stimulated myocardial glucose uptake in patients with Type 2 diabetes , most probably due to its suppression of the serum FFAs Persistent hyperglycemia secondary to insulin resistance and eventual insufficient insulin secretory capacity is the hallmark of type 2 diabetes mellitus . Resistance to insulin-stimulated glucose uptake is present in most patients with this disease ( 1 ) . Treatment is aim ed at reducing blood glucose levels to normal or near-normal values ( 2 , 3 ) . Diet and exercise are the first treatments of choice for patients with type 2 diabetes mellitus . However , as many as 95 % of those with newly diagnosed diabetes do not achieve adequate blood glucose control after a 3-month dietary intervention ( 4 ) , and initiation with oral antidiabetes therapy is then advocated . On the basis of patient profile and level of glycemic control , first-line monotherapy typically begins with sulfonylurea ( an insulin secretagogue ) or metformin , which inhibits hepatic gluconeogenesis ( 5 ) . When monotherapy fails to achieve optimal glycemic control , these agents are frequently prescribed in combination ( 6 ) . However , many patients continue to experience suboptimal control , resisting health professionals ' ultimate recommendation to begin insulin injection therapy ( 7 - 9 ) . Thiazolidinediones are a class of peroxisome proliferator-activated receptor- drugs that , unlike sulfonylureas and metformin , stimulate increased peripheral glucose disposal and reduce insulin resistance in the muscle , liver , and adipose tissue ( 10 - 15 ) . Studies have shown that troglitazone used as monotherapy or in combination with sulfonylurea and insulin improves glucose control ( 16 - 18 ) . The addition of an insulin-sensitizing agent , such as troglitazone , to complement the insulin-stimulatory and hepatic glucosesuppressive effects of sulfonylurea and metformin has been considered an attractive therapeutic alternative to insulin . However , whether a thiazolidinedione would be efficient at a stage of the disease when -cell secretion is failing ( 19 ) remains to be demonstrated . The current trial ( which was completed before troglitazone was withdrawn from the U.S. market because of hepatotoxicity ) was conducted to determine whether the addition of a thiazolidinedione , troglitazone , could decrease hemoglobin A1c levels and thereby delay or eliminate the need for insulin treatment in patients who did not achieve adequate glucose control despite combined therapy with sulfonylurea and metformin . Methods Patients This multicenter study was conducted at 16 sites in Canada . Study participants were required to be at least 40 years of age and to have type 2 diabetes mellitus according to the National Diabetes Data Group criteria ( 20 ) . Inadequate glycemic control was defined as having a hemoglobin A1c level of at least 0.085 ( 8.5 % ) despite undergoing at least 8 weeks of stable treatment with maximum tolerable doses of oral sulfonylurea and metformin .  Patients treated with less than 20 mg of glyburide and less than 1500 mg of metformin  were included only if documentation of intolerance to higher doses was available . Patients were ineligible if they had previously received long-term insulin treatment ( 3 days of treatment was allowed ) or were currently using fenfluramine or glucocorticoids ( these patients were excluded because of the negative effects of these drugs on insulin sensitivity ) . Patients were also ineligible if they had any of the following : serum creatinine concentration greater than 180 mol/L ( 2.0 mg/dL ) , alanine aminotransferase ( ALT ) level more than 2 times the upper limit of normal , uncontrolled hypertension , anemia , symptomatic angina , cardiac insufficiency , body mass index greater than 40 kg/m2 , or active cancer within 5 years of screening . Contraceptive use was required for women of childbearing potential . Patient volunteers gave written informed consent to participate in the study . An ethics committeeinstitutional review board at each study center approved the protocol . Study Design Patients were recruited if they had received a diagnosis of type 2 diabetes mellitus and were currently taking maximum-dose sulfonylurea and metformin . Patients at each study site who met the inclusion criteria were invited to participate . Upon acceptance , they entered a 4-week lead-in period and received placebo in addition to their current regimen of sulfonylurea and metformin . Patients were then r and omly assigned to receive , in a double-blind fashion , troglitazone , 400 mg/d , or a matching placebo of similar appearance and taste once daily for 24 weeks , in addition to current treatment with sulfonylurea and metformin . R and om assignment of patients occurred sequentially , following a single computer-generated r and omization schedule for the entire study with a block size of four . Medication was packaged according to the r and omization schedule and was allocated to centers in blocks of four . Investigators , patients , and the sponsor were blinded to treatment and primary glycemic measures . After 24 weeks of double-blind treatment , an open-label phase followed in which placebo recipients began taking troglitazone , 400 mg/d , and patients previously treated with troglitazone continued to receive it for an additional 24 weeks . Fasting plasma glucose level and biochemical measures of safety , including chemistry tests ( ALT and aspartate aminotransferase levels ) , hematologic tests , and urinalysis were performed at 4-week intervals throughout the study . Hemoglobin A1c level , total plasma insulin level , and lipid levels were measured at r and omization and at 4-week intervals beginning at week 12 . Self-monitoring of  blood glucose level was encouraged , and glucose meters were provided to all patients . Symptomatic hypoglycemic events were characterized by the type of intervention required to alleviate the event and by severity ( on the basis of a self-monitored blood glucose value obtained when symptomatic hypoglycemia was present ) .  Physical examination  and  12-lead electrocardiography  were performed for each patient as additional safety assessment s before r and omization and at the end of the double-blind and open-label studies . Patients were to be withdrawn at their own discretion or if a clinician judged that their glucose levels were acutely deleterious , if they did not adhere to the protocol ( that is , if they were < 80 % adherent to the study drug regimen ) , or if they had an intolerable adverse event . A central clinical laboratory ( Medical Research Laboratories , Highl and Heights , Kentucky ) performed all biochemical measurements for all study centers . Hemoglobin A1c levels were measured by automated ion-exchange high-performance liquid chromatography ( Bio-Rad Labs , Hercules , California ) , and insulin was measured by using a two-site immunoenzymometric assay ( sensitivity , 8 pmol/L ) . Triglyceride , total cholesterol , and plasma glucose levels ( hexokinase ) were measured by using enzymatic methods with a Hitachi 747 analyzer ( Hitachi Instruments , Inc. , San Jose , California ) . High-density lipoprotein cholesterol was isolated by chemical precipitation and was measured in the same way as total cholesterol . Low-density lipoprotein cholesterol level was calculated by using the equation of Friedewald and colleagues ( 21 ) . Statistical Analysis The sample calculation was based on a two-sided t-test , with a P value less than 0.05 indicating significance . Assuming that the st and ard deviation of hemoglobin A1c level was 0.017 ( 1.7 % ) , 62 patients per treatment group were needed to detect at least a 1 % difference between troglitazone-treated patients and placebo recipients at a power of 0.9 . Assuming a 25 % loss due to dropout , our goal was to r and omly assign a minimum of 85 patients to each treatment group . The analyses of efficacy for the double-blind study were performed according to the intention-to-treat method and included all patients who received at least one dose of troglitazone or placebo and had at least one follow-up visit . The last observations for patients were carried forward to impute missing values . The safety analyses also included all patients . The analyses of efficacy for the open-label study were performed by using summary statistics inclusive of all available data for patients who entered the open-label study . Statistical analyses were performed by using SAS software , version 6.12 ( SAS Institute , Inc. , Cary , North Carolina ) . Changes in levels of hemoglobin A1c , fasting plasma glucose , insulin , triglycerides , total cholesterol , high-density lipoprotein cholesterol , and low-density lipoprotein cholesterol from r and omization to the end of the double-blind study were analyzed by using analysis of covariance , with treatment and study center as factors and the baseline value as the covariate . All statistical tests were two-sided ( = 0.05 ) . Exploratory analyses to investigate the effects of age , sex , menopausal status , and ethnicity were also conducted by using analysis of covariance , with center and treatment as factors and the baseline value as the covariate . The proportion of patients achieving American Diabetes Association glycemic control targets in the two treatment groups was compared by using the Fisher exact test with data pooled across study centers because some centers had insufficient data . Safety variables were evaluated by using summary statistics . Role of the Funding Source Parke-Davis provided funding and facilitated the data collection and analysis for this study and approved su bmi ssion of the manuscript for publication . The authors had final authority over the decision to su bmi t the manuscript for publication . Results Patients Baseline demographic and disease-related characteristics were similar for the two treatment groups ( Table 1 ) . Two hundred patients were r and omly assigned , and 178 patients ( 92 in the troglitazone group and 86 in the placebo group ) completed the double-blind study ( Figure 1 ) . A small percentage of patients withdrew early , but these withdrawals were not concentrated at any study center and were evenly distributed across the two treatment groups . The only noted difference was in patient BACKGROUND Insulin-resistant states , including type 2 diabetes ( T2D ) and prediabetes , are associated with elevated cardiovascular ( CV ) risk . Aleglitazar is a dual peroxisome proliferator-activated receptor α/γ agonist with favorable insulin-sensitizing and glucose-lowering actions , favorable effects on blood lipids , and an acceptable safety profile in short-time studies . Therefore , it was hypothesized that aleglitazar would reduce CV morbidity and mortality in patients with T2D mellitus and prediabetes ( defined as glycosylated hemoglobin ≥5.7 % to < 6.5 % ) with previous CV complications . STUDY DESIGN ALEPREVENT was a phase III , multicenter , r and omized , double-blind , trial comparing aleglitazar 150 μg or placebo daily in patients with T2D or prediabetes with established , stable CV disease . The intended sample size was 19,000 with a primary efficacy measure of major adverse CV events . However , the trial was halted prematurely after 1,999 patients had been r and omized because of futility and an unfavorable benefit risk ratio in another CV outcomes trial evaluating aleglitazar . RESULTS At study termination after 58 ± 38 days of treatment , data had been collected from 1,996 patients ( 1,581 with T2D and 415 with pre-T2D ) . Despite the brief duration of treatment , aleglitazar induced favorable changes in glycosylated hemoglobin and blood lipids , similar for participants with T2D or prediabetes . However , compared with placebo , aleglitazar  increased the incidence of hypoglycemia ( 86 vs 166 ; P < .0001 ) , and muscular events ( 3 vs12 ; P = .012 ) . CONCLUSIONS Even within a short duration of exposure , aleglitazar was associated with excess adverse events , corroborating the findings of a larger and longer trial in T2D . Coupled with the previous failure of several other peroxisome proliferator-activated receptor α/γ activators , this class now holds little promise for CV therapeutics OBJECTIVE The development of new insulin sensitizers is an unmet need for the treatment of type 2 diabetes . We investigated the effect of GFT505 , a dual peroxisome proliferator – activated receptor (PPAR)-α/δ agonist , on peripheral and hepatic insulin sensitivity . RESEARCH DESIGN AND METHODS Twenty-two abdominally obese insulin-resistant males ( homeostasis model assessment of insulin resistance > 3 ) were r and omly assigned in a r and omized crossover study to subsequent 8-week treatment periods with GFT505 ( 80 mg/day ) or placebo , followed by a two-step hyperinsulinemic-euglycemic insulin clamp with a glucose tracer to calculate endogenous glucose production ( EGP ) . The primary end point was the improvement in glucose infusion rate ( GIR ) . Gene expression analysis was performed on skeletal muscle biopsy specimens . RESULTS GFT505  improved peripheral insulin sensitivity , with a 21 % ( P = 0.048 ) increase of the GIR at the second insulin infusion period . GFT505 also enhanced hepatic insulin sensitivity , with a 44 % ( P = 0.006 ) increase of insulin suppression of EGP at the first insulin infusion period . Insulin-suppressed plasma free fatty acid concentrations were significantly reduced on GFT505 treatment ( 0.21 ± 0.07 vs. 0.27 ± 0.11 mmol/L ; P = 0.006 ) . Neither PPARα nor PPARδ target genes were induced in skeletal muscle , suggesting a liver-targeted action of GFT505 . GFT505 significantly reduced fasting plasma triglycerides ( −21 % ; P = 0.003 ) and LDL cholesterol ( −13 % ; P = 0.0006 ) , as well as liver enzyme concentrations ( γ-glutamyltranspeptidase : −30.4 % , P = 0.003 ; alanine aminotransferase : −20.5 % , P = 0.004 ) . There was no safety concern or any indication of PPARγ activation with GFT505 . CONCLUSIONS The dual PPARα/δ agonist GFT505 is a liver-targeted insulin-sensitizer that is a promising drug c and i date for the treatment of type 2 diabetes and nonalcoholic fatty liver disease Whereas thiazolidinediones ( TZDs ) are known to rapidly improve insulin action in animals , short duration s of TZD therapy have never been studied in humans . Among the many known actions of TZDs , increased circulating levels of the high molecular weight ( HMW ) multimer of adiponectin may be an important insulin-sensitizing mechanism . We examined the effects of only 21 days of 45 mg of pioglitazone ( P+ ) versus placebo ( P- ) in nine subjects with type 2 diabetes ( HbA(1c ) , 10.9 + /- 0.6 % ; BMI , 31.9 + /- 1.5 kg/m(2 ) ) .  Total adiponectin levels increased by approximately twofold in P+ in association with increased adipose tissue gene expression . However , plasma free fatty acid and glucose levels were unchanged , and there were only minimal changes in other " adipokines . " Glucose fluxes ( [3-(3)H]glucose infusion ) were measured during 6-h euglycemic ( 5 mmol/l ) " pancreatic clamp " studies ( somatostatin/glucagon/growth hormone ) with stepped insulin levels . Pioglitazone induced marked decreases in endogenous glucose production ( P+ = 0.9 + /- 0.1 vs. P- = 1.7 + /- 0.3 mg . kg(-1 ) . min(-1 ) ; P < 0.05 ) at physiologic hyperinsulinemia ( approximately 50 microU/ml ) , which was highly correlated with an increased ratio of HMW adiponectin/total levels ( r(2 ) = 0.90 ) . Maximal insulin stimulation ( approximately 400 microU/ml ) revealed pioglitazone-associated increases in glucose uptake ( P+ = 10.5 + /- 0.9 vs. P- = 8.9 + /- 0.8 mg . kg(-1 ) . min(-1 ) ; P < 0.05 ) , which did not correlate with HMW or total adiponectin levels . Thus , only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes . Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents Type 2 diabetes frequently results from progressive failure of pancreatic beta-cell function in the presence of chronic insulin resistance . We tested whether chronic amelioration of insulin resistance would preserve pancreatic beta-cell function and delay or prevent the onset of type 2 diabetes  in high-risk Hispanic women . Women with previous gestational diabetes were r and omized to placebo ( n = 133 ) or the insulin-sensitizing drug troglitazone ( 400 mg/day ; n = 133 ) administered in double-blind fashion . Fasting plasma glucose was measured every 3 months , and oral glucose tolerance tests ( OGTTs ) were performed annually to detect diabetes . Intravenous glucose tolerance tests ( IVGTTs ) were performed at baseline and 3 months later to identify early metabolic changes associated with any protection from diabetes . Women who did not develop diabetes during the trial returned for OGTTs and IVGTTs 8 months after study medications were stopped . During a median follow-up of 30 months on blinded medication , average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1 and 5.4 % in women assigned to placebo and troglitazone , respectively ( P < 0.01 ) . Protection from diabetes in the troglitazone group 1 ) was closely related to the degree of reduction in endogenous insulin requirements 3 months after r and omization , 2 ) persisted 8 months after study medications were stopped , and 3 ) was associated with preservation of beta-cell compensation for insulin resistance . Treatment with troglitazone delayed or prevented the onset of type 2 diabetes in high-risk Hispanic women . The protective effect was associated with the preservation of pancreatic beta-cell function and appeared to be mediated by a reduction in the secretory dem and s placed on beta-cells by chronic insulin resistance OBJECTIVE To assess the interaction between insulin resistance and endothelial function and the optimal treatment strategy addressing cardiovascular risk in polycystic ovary syndrome . DESIGN R and omized controlled trial . SETTING Controlled clinical study . PATIENT(S ) Overweight age- and body mass index-matched women with polycystic ovary syndrome . INTERVENTION(S ) Six months metformin ( 1 g two times per day , n = 36 ) or oral contraceptive pill ( OCP ) ( 35 microg ethinyl E(2)-2 mg cytoproterone acetate , n = 30 ) . MAIN OUTCOME MEASURE(S ) Fasting and oral glucose tolerance test glucose and insulin levels , endothelial function ( flow-mediated dilation , asymmetric dimethylarginine , plasminogen activator inhibitor-1 , von Willebr and factor ) , inflammatory markers ( high-sensitivity C-reactive protein ) , lipids , and hyper and rogenism . RESULT ( S ) The OCP increased levels of glucose and insulin on oral glucose tolerance test , high-sensitivity C-reactive protein , triglycerides , and sex-hormone binding globulin and decreased levels of low-density lipoprotein cholesterol and T.  Metformin decreased levels of fasting insulin , oral glucose tolerance test insulin , high-density lipoprotein cholesterol , and high-sensitivity C-reactive protein . Flow-mediated dilation increased only with metformin ( + 2.2 % + /- 4.8 % ) , whereas asymmetric dimethylarginine decreased equivalently for OCP and metformin ( -0.3 + /- 0.1 vs. -0.1 + /- 0.1 mmol/L ) . Greater decreases in plasminogen activator inhibitor-1 occurred for the OCP than for metformin ( -1.8 + /- 1.6 vs. -0.7 + /- 1.7 U/mL ) . CONCLUSION ( S ) In polycystic ovary syndrome , metformin improves insulin resistance , inflammatory markers , and endothelial function . The OCP worsens insulin resistance and glucose homeostasis , inflammatory markers , and triglycerides and has neutral or positive endothelial effects . The effect of the OCP on cardiovascular risk in polycystic ovary syndrome is unclear Rosiglitazone , a thiazolidinedione , enhances peripheral insulin sensitivity in patients with type 2 diabetes . Because the synergic action of insulin and exercise has been shown to be decreased in insulin resistance , the aim of this study was to compare the effects of rosiglitazone and metformin on muscle insulin responsiveness at rest and during exercise in patients with type 2 diabetes . Therefore , 45 patients with newly diagnosed or diet-treated type 2 diabetes were r and omized for treatment with rosiglitazone ( 4 mg b.i.d . ) , metformin ( 1 g b.i.d . ) , or placebo in a 26-week double-blind trial . Skeletal muscle glucose uptake was measured using fluorine-18-labeled fluoro-deoxy-glucose and positron emission tomography ( PET ) during euglycemic-hyperinsulinemic clamp and one-legged exercise before and after the treatment period . Rosiglitazone ( P < 0.05 ) and metformin ( P < 0.0001 ) treatment lowered the mean glycosylated hemoglobin . The skeletal muscle glucose uptake was increased by 38 % ( P < 0.01 ) and whole-body glucose uptake by 44 % in the rosiglitazone group . Furthermore , the exercise-induced increment during insulin stimulation was enhanced by 99 % ( P < 0.0001 ) . No changes were observed in skeletal muscle or whole-body insulin sensitivity in the metformin group . In conclusion , rosiglitazone but not metformin 1 ) improves insulin responsiveness in resting skeletal muscle and 2 ) doubles the insulin-stimulated glucose uptake rate during physical exercise in patients with type 2 diabetes . Our results suggest that rosiglitazone improves synergic action of insulin and exercise AIMS Assess insulin sensitivity after treatment with a selective PPAR-alpha agonist compared to an HMG CoA reductase inhibitor in human subjects with type 2 diabetes mellitus . METHODS Thirteen subjects with Type 2 diabetes mellitus were studied in a double-blind crossover design with 4-week placebo run-in and washout and 12-week treatment periods , r and omised to micronised fenofibrate 267 mg or atorvastatin 10 mg daily followed by the alternate drug in the second period . Insulin resistance was measured using the isoglycaemic hyperinsulinaemic clamp method with isotope dilution . RESULTS Weight , physical activity and other medications did not change . Total cholesterol ( mean + /- st and ard error ) was 4.60+/-0.21 versus 3.9+/-0.22 mmol/L after fenofibrate and atorvastatin respectively , p<0.05 . LDL was 2.70+/-0.19 versus 1.95+/-0.23 mmol/L , p<0.05 and triglyceride 1.64+/-0.23 versus 1.84+/-0.26 mmol/L , p<0.05 . Insulin-stimulated whole-body glucose disposal ( 35.4+/-3.1 versus 33.2+/-3.0 μmol/kg/min ) and nadir endogenous glucose production ( 6.2+/-1.4 versus 7.0+/-1.1 μmol/kg/min ) revealed no significant differences in effects of the treatments . CONCLUSIONS In human subjects with Type 2 diabetes mellitus there were characteristic differences in lipid profile changes but no difference in insulin sensitivity after treatment with micronised fenofibrate compared to atorvastatin . This study finds no evidence of increased insulin sensitivity using this selective PPAR-alpha agonist over a commonly used statin at these doses To examine the molecular mechanisms by which plasma amino acid elevation impairs insulin action , we studied seven healthy men twice in r and om order during infusion of an amino acid mixture or saline ( total plasma amino acid approximately 6 vs. approximately 2 mmol/l ) . Somatostatin-insulin-glucose clamps created conditions of low peripheral hyperinsulinemia ( approximately 100 pmol/l , 0 - 180 min ) and pr and ial-like peripheral hyperinsulinemia ( approximately 430 pmol/l , 180 - 360 min ) . At low peripheral hyperinsulinemia , endogenous glucose production ( EGP ) did not change during amino acid infusion but decreased by approximately 70 % during saline infusion ( EGP(150 - 180 min ) 11 + /- 1 vs. 3 + /- 1 mumol . kg(-1 ) . min(-1 ) , P = 0.001 ) . Pr and ial-like peripheral hyperinsulinemia completely suppressed EGP during both protocol s , whereas whole-body rate of glucose disappearance ( R(d ) ) was approximately 33 % lower during amino acid infusion ( R(d ) ( 330 - 360 min ) 50 + /- 4 vs. 75 + /- 6 mumol . kg(-1 ) . min(-1 ) , P = 0.002 ) indicating insulin resistance . In skeletal muscle biopsies taken before and after pr and ial-like peripheral hyperinsulinemia , plasma amino acid elevation markedly increased the ability of insulin to activate S6 kinase 1 compared with saline infusion ( approximately 3.7- vs. approximately 1.9-fold over baseline ) . Furthermore , amino acid infusion increased the inhibitory insulin receptor substrate-1 phosphorylation at Ser312 and Ser636/639 and decreased insulin-induced phosphoinositide 3-kinase activity . However , plasma amino acid elevation failed to reduce insulin-induced Akt/protein kinase B and glycogen synthase kinase 3alpha phosphorylation . In conclusion , amino acids impair 1 ) insulin-mediated suppression of glucose production and 2 ) insulin-stimulated glucose disposal in skeletal muscle . Our results suggest that overactivation of the mammalian target of rapamycin/S6 kinase 1 pathway and inhibitory serine phosphorylation of insulin receptor substrate-1 underlie the impairment of insulin action in amino acid-infused humans Abstract Aims / Introduction Pemafibrate is a novel selective peroxisome proliferator‐activated receptor‐α modulator with potent triglyceride‐lowering and high‐density lipoprotein cholesterol‐raising effects . We showed that pemafibrate decreased the homeostatic model assessment for insulin resistance in patients with dyslipidemia . To investigate how pemafibrate improves insulin sensitivity , we used a hyperinsulinemic‐euglycemic clamp technique to determine the splanchnic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance . Material s and Methods A total of 27 patients with hypertriglyceridemia and insulin resistance were r and omly assigned to receive pemafibrate ( 0.4 mg/day , b.i.d . ) or placebo treatment for 12 weeks . The hyperinsulinemic‐euglycemic clamp test combined with oral glucose loading was carried out at weeks 0 and 12 to evaluate the splanchnic and peripheral glucose uptake . Results Pemafibrate , but not the placebo , significantly increased the splanchnic glucose uptake rate from baseline ( 19.6 ± 5.9 % with P = 0.005 and 2.1 ± 7.4 % with P = 0.78 , respectively ) , although no significant difference between the groups was observed ( P = 0.084 ) . Conversely , peripheral glucose uptake rate was not significantly altered . Pemafibrate , compared with the placebo , significantly decreased plasma triglycerides ( −61.4 ± 16.4 % vs −2.5 ± 41.4 % , P = 0.001 ) , free fatty acids ( −24.8 ± 23.2 % vs 2.0 ± 26.8 % , P = 0.016 ) and gamma‐glutamyl transpeptidase ( −30 ± 46 vs 10 ± 19 U/L , P = 0.009 ) levels , and significantly increased fibroblast growth factor 21 ( 457.7 ± 402.1 vs −41.7 ± 37.4 pg/mL , P = 0.007 ) levels . Conclusions Pemafibrate  increased splanchnic glucose uptake from baseline in patients with hypertriglyceridemia The effect of metformin or rosiglitazone monotherapy versus placebo on insulin signaling and gene expression in skeletal muscle of patients with newly diagnosed type 2 diabetes was determined . A euglycemic-hyperinsulinemic clamp , combined with skeletal muscle biopsies and glucose uptake measurements over rested and exercised muscle , was performed before and after 26 weeks of metformin ( n = 9 ) , rosiglitazone ( n = 10 ) , or placebo ( n = 11 ) treatment . Insulin-mediated whole-body and leg muscle glucose uptake was enhanced 36 and 32 % , respectively , after rosiglitazone ( P < 0.01 ) but not after metformin or placebo treatment . Insulin increased insulin receptor substrate 1 ( IRS-1 ) tyrosine phosphorylation , IRS-1-associated phosphatidylinositol ( PI ) 3-kinase activity , and phosphorylation of Akt Ser473 and AS160 , a newly described Akt substrate that plays a role in GLUT4 exocytosis , approximately 2.3 fold before treatment . These insulin signaling parameters were unaltered after metformin , rosiglitazone , or placebo treatment . Expression of selected genes involved in glucose and fatty acid metabolism in skeletal muscle was unchanged between the treatment groups . Low-intensity acute exercise increased insulin-mediated glucose uptake but was without effect on insulin signaling . In conclusion , the insulin-sensitizing effects of rosiglitazone are independent of enhanced signaling of IRS-1/PI 3-kinase/Akt/AS160 in patients with newly diagnosed type 2 diabetes OBJECTIVES This study was design ed to assess the effect of metformin on impaired endothelial function in type 2 diabetes mellitus . BACKGROUND Abnormalities in vascular endothelial function are well recognized among patients with type 2 ( insulin-resistant ) diabetes mellitus . Insulin resistance itself may be central to the pathogenesis of endothelial dysfunction . The effects of metformin , an antidiabetic agent that improves insulin sensitivity , on endothelial function have not been reported . METHODS Subjects with diet-treated type 2 diabetes but without the confounding collection of cardiovascular risk factors seen in the metabolic syndrome were treated with metformin 500 mg twice daily ( n = 29 ) or placebo ( n = 15 ) for 12 weeks . Before and after treatment , blood flow responses to intraarterial administration of endothelium-dependent ( acetylcholine ) , endothelium-independent ( sodium nitroprusside ) and nitrate-independent ( verapamil ) vasodilators were measured using forearm plethysmography . Whole-body insulin resistance was assessed on both occasions using the homeostasis model ( HOMA-IR ) . RESULTS Subjects who received metformin demonstrated statistically significant improvement in acetylcholine-stimulated flows compared with those treated with placebo ( p = 0.0027 by 2-way analysis of variance ) , whereas no significant effect was seen on nitroprusside-stimulated ( p = 0.27 ) or verapamil-stimulated ( p = 0.40 ) flows . There was a significant improvement in insulin resistance with metformin ( 32.5 % reduction in HOMA-IR , p = 0.01 ) , and by stepwise multivariate analysis insulin resistance was the sole predictor of endothelium-dependent blood flow following treatment ( r = -0.659 , p = 0.0012 ) . CONCLUSIONS Metformin treatment improved both insulin resistance and endothelial function , with a strong statistical link between these variables . This supports the concept of the central role of insulin resistance in the pathogenesis of endothelial dysfunction in type 2 diabetes mellitus . This has important implication s for the investigation and treatment of vascular disease in patients with type 2 diabetes mellitus OBJECTIVES Our aim was to investigate if the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone modulates inflammation through PPARalpha mechanisms . BACKGROUND The thiazolidinediones ( TZDs ) pioglitazone and rosiglitazone are insulin-sensitizing PPARgamma agonists used to treat type 2 diabetes ( T2DM ) . Despite evidence for TZDs limiting inflammation and atherosclerosis , questions exist regarding differential responses to TZDs . In a double-blinded , placebo-controlled 16-week trial among recently diagnosed T2DM subjects ( n = 34 ) , pioglitazone-treated subjects manifested lower triglycerides and lacked the increase in soluble vascular cell adhesion molecules (sVCAM)-1 evident in the placebo group . Previously we reported PPARalpha but not PPARgamma agonists could repress VCAM-1 expression . Since both triglyceride-lowering and VCAM-1 repression characterize PPARalpha activation , we studied pioglitazone 's effects via PPARalpha . METHODS Pioglitazone effects on known PPARalpha responses -- lig and binding domain activation and PPARalpha target gene expression -- were tested in vitro and in vivo , including in wild-type and PPARalpha-deficient cells and mice , and compared with the effects of other PPARgamma ( rosiglitazone ) and PPARalpha ( WY14643 ) agonists . RESULTS Pioglitazone repressed endothelial TNFalpha-induced VCAM-1 messenger ribonucleic acid expression and promoter activity , and induced hepatic IkappaBalpha in a manner dependent on both pioglitazone exposure and PPARalpha expression . Pioglitazone also activated the PPARalpha lig and binding domain and induced PPARalpha target gene expression , with in vitro effects that were most pronounced in endothelial cells . In vivo , pioglitazone administration modulated sVCAM-1 levels and IkappaBalpha expression in wild-type but not PPARalpha-deficient mice . CONCLUSIONS Pioglitazone regulates inflammatory target genes in hepatic ( IkappaBalpha ) and endothelial ( VCAM-1 ) setting s in a PPARalpha-dependent manner . These data offer novel mechanisms that may underlie distinct TZD responses Background —Recent studies have shown that type 2 diabetes is preventable by both lifestyle interventions and medications that influence primary glucose metabolism . Whether pharmacological interventions that influence primary lipid metabolism can also delay development of type 2 diabetes is unknown . The goal of this study was to evaluate the effect of the peroxisome proliferator – activated receptor lig and bezafibrate on the progression of impaired fasting glucose phase to type 2 diabetes in patients with coronary artery disease over a 6.2-year follow-up period . Methods and Results —The study sample comprised 303 nondiabetic patients 42 to 74 years of age with a fasting blood glucose level of 110 to 125 mg/dL ( 6.1 to 6.9 mmol/L ) . The patients received either 400 mg bezafibrate retard ( 156 patients ) or placebo ( 147 patients ) once a day . No patients were using statins , and use of ACE inhibitors , which also reduce diabetes incidence , was relatively low . During follow-up , development of new-onset diabetes was recorded in 146 patients : in 80 ( 54.4 % ) from the placebo group and 66 ( 42.3 % ) from the bezafibrate group ( P = 0.04 ) . The mean time until onset of new diabetes was significantly delayed in patients on bezafibrate compared with patients on placebo : 4.6±2.3 versus 3.8±2.6 years ( P = 0.004 ) . Multivariate analysis identified bezafibrate treatment as an independent predictor of reduced risk of new diabetes development ( hazard ratio , 0.70 ; 95 % CI , 0.49 to 0.99 ) . Other significant variables associated with future overt type 2 diabetes in patients with impaired fasting glucose were total cholesterol level ( hazard ratio , 1.22 ; 95 % CI 1.0 to 1.51 ) and body mass index ( hazard ratio , 1.10 ; 95 % CI , 1.05 to 1.16 ) . Conclusions —Bezafibrate reduces the incidence and delays the onset of type 2 diabetes in patients with impaired fasting glucose . Whether the combination of bezafibrate with other recommended drugs for secondary prevention ( statins and ACE inhibitors ) would be as efficacious as suggested by our results remains to be determined OBJECTIVE Therapies with metformin , sulfonylureas , or insulin improve glycemic control in the short term but do not prevent progressive islet beta-cell failure or long-term deterioration in glycemia . Our goal was to evaluate , in patients recently diagnosed with type 2 diabetes ( <3 years ) , the long-term efficacy of monotherapy with rosiglitazone on glycemic control and on the progression of pathophysiological abnormalities associated with type 2 diabetes as compared with metformin or glyburide monotherapy . RESEARCH DESIGN AND METHODS A Diabetes Outcome Progression Trial ( ADOPT ) is a r and omized , double-blind , parallel-group study consisting of a screening visit , a 4-week placebo run-in , a 4-year treatment period , and an observational follow-up of approximately 3,600 drug-naïve patients with type 2 diabetes diagnosed within the previous 3 years . After run-in , patients will be r and omized to rosiglitazone , glyburide , or metformin titrated to the maximum effective daily doses ( 8 mg rosiglitazone , 15 mg glyburide , or 2 g metformin ) . The primary outcome is time to monotherapy failure , defined as the time following titration to the maximal effective or tolerated dose when fasting plasma glucose exceeds 180 mg/dl ( 10 mmol/l ) . Secondary outcomes include measures of islet beta-cell function , insulin sensitivity , dyslipidemia , changes in urinary albumin excretion , plasminogen activator inhibitor-1 antigen , fibrinogen , and C-reactive protein . Safety and tolerability will also be evaluated . Patient-reported outcomes and re source utilization data will be collected and analyzed . CONCLUSIONS ADOPT will provide data on the effect of mechanistically differing treatment options on metabolic control , beta-cell function , and markers of macrovascular disease risk in type 2 diabetes AIMS /HYPOTHESIS Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1 . Chronic vildagliptin treatment decreases postpr and ial glucose levels and reduces hemoglobin A1c in type 2 diabetic patients . However , little is known about the mechanism(s ) by which vildagliptin promotes reduction in plasma glucose concentration . METHODS Sixteen patients with type 2 diabetes ( age , 48+/-3 yr ; body mass index , 34.4+/-1.7 kg/m2 ; hemoglobin A1c , 9.0+/-0.3 % ) participated in a r and omized , double-blind , placebo-controlled trial . On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test ( MTT ) performed with double tracer technique ( 3-(3)H-glucose iv and 1-(14)C-glucose orally ) . RESULTS After vildagliptin , suppression of endogenous glucose production ( EGP ) during 6-h MTT was greater than with placebo ( 1.02+/-0.06 vs. 0.74+/-0.06 mg.kg-1.min-1 ; P=0.004 ) , and insulin secretion rate increased by 21 % ( P=0.003 ) despite significant reduction in mean plasma glucose ( 213+/-4 vs. 230+/-4 mg/dl ; P=0.006 ) . Consequently , insulin secretion rate ( area under the curve ) divided by plasma glucose ( area under the curve ) increased by 29 % ( P=0.01 ) . Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin ( P<0.02 ) . The decline in EGP was positively correlated ( r=0.55 ; P<0.03 ) with the decrease in fasting plasma glucose ( change=-14 mg/dl ) . CONCLUSIONS During MTT , vildagliptin augments insulin secretion and inhibits glucagon release , leading to enhanced suppression of EGP . During the postpr and ial period , a single dose of vildagliptin reduced plasma glucose levels by enhancing suppression of EGP
Results Both TZDs and metformin  enhance insulin suppression of endogenous glucose production and fasting plasma glucose clearance .
TZDs , but not metformin , also improve insulin-mediated glucose uptake at all insulin levels .
Conclusions /interpretationIn patients with type 2 diabetes , metformin improves fasting hepatic insulin sensitivity and glucose clearance ; TZDs improve fasting hepatic insulin sensitivity and glucose clearance , and potentiate glucose disposal under insulinised conditions
Aims /hypothesisInsulin resistance , which manifests itself as endogenous glucose overproduction and reduced insulin-mediated glucose uptake , is a core defect in type 2 diabetes .
Metformin and the peroxisome proliferator-activated receptor-γ agonists , the thiazolidinediones ( TZDs ) , both lower glucose , although their mechanism of action is still subject to debate .
This review analyses the evidence relevant to these mechanisms in vivo .