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. Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Dual Peroxisome Proliferator–Activated Receptor α/δ Agonist GFT505 Improves Hepatic and Peripheral Insulin Sensitivity in Abdominally Obese Subjects Enhancement of insulin-stimulated myocardial glucose uptake in patients with Type 2 diabetes treated with rosiglitazone. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. The Effect of Adding Exenatide to a Thiazolidinedione in Suboptimally Controlled Type 2 Diabetes Rosiglitazone but not metformin enhances insulin- and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes. Metformin Based Dual-Combination Therapies in Drug Naïve Type 2 Diabetic Patients 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. Effect of peroxisome proliferator-activated receptor gamma agonist treatment on subclinical atherosclerosis in patients with insulin-requiring type 2 diabetes. The effects of rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, on markers of endothelial cell activation, C-reactive protein, and fibrinogen levels in non-diabetic coronary artery disease patients. 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 Exenatide alters myocardial glucose transport and uptake depending on insulin resistance and increases myocardial blood flow in patients with type 2 diabetes. Effects of the dual peroxisome proliferator-activated receptor activator aleglitazar in patients with Type 2 Diabetes mellitus or prediabetes. Analysis of the relationship between the Pro12Ala variant in the PPAR-gamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. Insulin action is associated with endothelial function in hypertension and type 2 diabetes. Defects in insulin receptor signaling in vivo in the polycystic ovary syndrome (PCOS). Effects of metformin and rosiglitazone treatment on insulin signaling and glucose uptake in patients with newly diagnosed type 2 diabetes: a randomized controlled study. Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. 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
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 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 We evaluated the effects of rosiglitazone ( 4 mg b.i.d . ) and metformin ( 1 g b.i.d . ) monotherapy for 26 weeks on adipose tissue insulin-stimulated glucose uptake in patients ( n = 41 ) with type 2 diabetes . Before and after the treatment , glucose uptake was measured using 2-[(18)F]fluoro-2-deoxyglucose and positron emission tomography and adipose tissue masses were quantified using magnetic resonance imaging . Rosiglitazone improved insulin-stimulated whole-body glucose uptake by 44 % ( P < 0.01 vs. placebo ) . Mean body weight was unchanged in the rosiglitazone group , while it decreased by 2.0 kg in the metformin group ( P < 0.05 vs. placebo ) . In visceral adipose tissue , glucose uptake increased by 29 % ( from 17.8 + /- 2.0 to 23.0 + /- 2.6 micro mol x kg(-1 ) x min(-1 ) , P < 0.05 vs. placebo ) in the rosiglitazone group but to a lesser extent ( 17 % ) in the metformin group ( from 16.2 + /- 1.5 to 18.9 + /- 1.7 micro mol x kg(-1 ) x min(-1 ) , P < 0.05 vs. baseline ) . Because the visceral adipose tissue mass simultaneously decreased with both treatments ( P < 0.05 ) , no change was observed in total visceral glucose uptake per depot . Rosiglitazone significantly enhanced glucose uptake in the femoral subcutaneous area , either when expressed per tissue mass ( from 10.8 + /- 1.2 to 17.1 + /- 1.7 micro mol x kg(-1 ) x min(-1 ) , P < 0.01 vs. placebo ) or per whole-fat depot ( P < 0.05 vs. placebo ) . In conclusion , metformin treatment result ed in improvement of glycemic control without enhancement of peripheral insulin sensitivity . The improved insulin sensitivity of the nonabdominal subcutaneous adipose tissue during treatment with rosiglitazone partly explains the enhanced whole-body insulin sensitivity and underlies the central role of adipose tissue for action of peroxisome proliferator-activated receptor gamma agonist in vivo The insulin-sensitizing effects of thiazolidinediones are thought to be mediated through peroxisome proliferator-activated receptor-gamma , a nuclear receptor that is highly abundant in adipose tissue . It has been reported that adipocytes secrete a variety of proteins , including tumor necrosis factor-alpha , resistin , plasminogen activator inhibitor-1 , and adiponectin . Adiponectin is a fat cell-secreted protein that has been reported to increase fat oxidation and improve insulin sensitivity . Our aim was to study the effects of troglitazone on adiponectin levels in lean , obese , and diabetic subjects . Ten diabetic and 17 nondiabetic subjects ( 8 lean , BMI < 27 kg/m(2 ) and 9 obese , BMI > 27 kg/m(2 ) ) participated in the study . All subjects underwent an 80 mU. m(-2 ) . min(-1 ) hyperinsulinemic-euglycemic glucose clamp before and after 3 months ' treatment with the thiazolidinedione ( TZD ) troglitazone ( 600 mg/day ) . Fasting plasma glucose significantly decreased in the diabetic group after 12 weeks of treatment compared with baseline ( 9.1 + /- 0.9 vs. 11.1 + /- 0.9 mmol/l , P < 0.005 ) but was unchanged in the lean and obese subjects . Fasting insulin for the entire group was significantly lower than baseline ( P = 0.02 ) after treatment . At baseline , glucose disposal rate ( R(d ) ) was lower in the diabetic subjects ( 3.4 + /- 0.5 mg . kg(-1 ) . min(-1 ) ) than in the lean ( 12.3 + /- 0.4 ) or obese subjects ( 6.7 + /- 0.7 ) ( P < 0.001 for both ) and was significantly improved in the diabetic and obese groups ( P < 0.05 ) after treatment , and it remained unchanged in the lean subjects . Baseline adiponectin levels were significantly lower in the diabetic than the lean subjects ( 9.0 + /- 1.7 vs. 16.7 + /- 2.7 micro g/ml , P = 0.03 ) and rose uniformly in all subjects ( 12.2 + /- 2.3 vs. 25.7 + /- 2.6 micro g/ml , P < 10(-4 ) ) after treatment , with no significant difference detected among the three groups . During the glucose clamps , adiponectin levels were suppressed below basal levels in all groups ( 10.2 + /- 2.3 vs. 12.2 + /- 2.3 micro g/ml , P < 0.01 ) . Adiponectin levels correlated with R(d ) ( r = 0.46 , P = 0.016 ) and HDL cholesterol levels ( r = 0.59 , P < 0.001 ) and negatively correlated with fasting insulin ( r = -0.39 , P = 0.042 ) and plasma triglyceride ( r = -0.61 , P < 0.001 ) . Our findings show that TZD treatment increased adiponectin levels in all subjects , including normal subjects in which no other effects of TZDs are observed . Insulin also appears to suppress adiponectin levels . We have confirmed these results in normal rats . These findings suggest that adiponectin can be regulated by obesity , diabetes , TZDs , and insulin , and it may play a physiologic role in enhancing insulin sensitivity 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 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 Both rosiglitazone and metformin increase hepatic insulin sensitivity , but their mechanism of action has not been compared in humans . The objective of this study was to compare the effects of rosiglitazone and metformin treatment on liver fat content , hepatic insulin sensitivity , insulin clearance , and gene expression in adipose tissue and serum adiponectin concentrations in type 2 diabetes . A total of 20 drug-naive patients with type 2 diabetes ( age 48 + /- 3 years , fasting plasma glucose 152 + /- 9 mg/dl , BMI 30.6 + /- 0.8 kg/m2 ) were treated in a double-blind r and omized fashion with either 8 mg rosiglitazone or 2 g metformin for 16 weeks . Both drugs similarly decreased HbA1c , insulin , and free fatty acid concentrations . Body weight decreased in the metformin ( 84 + /- 4 vs. 82 + /- 4 kg , P < 0.05 ) but not the rosiglitazone group . Liver fat ( proton spectroscopy ) was decreased with rosiglitazone by 51 % ( 15 + /- 3 vs. 7 + /- 1 % , 0 vs. 16 weeks , P = 0.003 ) but not by metformin ( 13 + /- 3 to 14 + /- 3 % , NS ) . Rosiglitazone ( 16 + /- 2 vs. 20 + /- 1 ml.kg(-1).min(-1 ) , P = 0.02 ) but not metformin increased insulin clearance by 20 % . Hepatic insulin sensitivity in the basal state increased similarly in both groups . Insulin-stimulated glucose uptake increased significantly with rosiglitazone but not with metformin .  Serum adiponectin concentrations increased by 123 % with rosiglitazone but remained unchanged during metformin treatment . The decrease of serum adiponectin concentrations correlated with the decrease in liver fat ( r = -0.74 , P < 0.001 ) . Rosiglitazone but not metformin significantly increased expression of peroxisome proliferator-activated receptor-gamma , adiponectin , and lipoprotein lipase in adipose tissue . In conclusion , rosiglitazone but not metformin decreases liver fat and increases insulin clearance . The decrease in liver fat by rosiglitazone is associated with an increase in serum adiponectin concentrations . Both agents increase hepatic insulin sensitivity , but only rosiglitazone increases peripheral glucose uptake Context The effects of adding exenatide to thiazolidinediones ( TZDs ) for treating type 2 diabetes are not clear . Contribution The investigators of this double-blind trial r and omly assigned 233 adults with type 2 diabetes that was suboptimallycontrolled with TZD ( with or without metformin )  to twice-daily injections of exenatide or placebo . At 16 weeks , exenatide reduced hemoglobin A1c levels ( mean difference , 0.98 % ) , fasting glucose levels ( mean difference , 1.69 mmol/L [ 30.5 mg/dL ] ) , and body weight ( mean difference , 1.51 kg ) more than placebo . More patients in the exenatide group than in the placebo group had nausea ( 40 % vs. 15 % ) and vomiting ( 13 % vs. 1 % ) . Implication s Adding exenatide to TZD modestly improves glycemic control and reduces body weight but causes nausea and vomiting in some patients . The Editors Exenatide is the first in a new class of medications called incretin mimetics that share several glucoregulatory effects with the incretin hormone glucagon-like peptide-1 and have been shown to bind the glucagon-like peptide-1 receptor in vitro ( 14 ) . Consequently , exenatide exerts glucoregulatory effects by enhancing glucose-dependent insulin secretion ( 57 ) , inhibiting inappropriately elevated glucagon secretion ( 8 , 9 ) , slowing gastric emptying ( 810 ) , and reducing food intake ( 10 ) . Exenatide therapy has also been shown to result in moderate weight reduction ( 11 ) . In addition , 82 weeks of exenatide therapy in an open-label extension trial result ed in weight loss associated with favorable effects on several cardiovascular risk factors , including triglyceride level , high-density lipoprotein cholesterol level , and diastolic blood pressure ( 12 ) . Insulin-sensitizing thiazolidinediones ( TZDs ) are widely used for treating type 2 diabetes . These peroxisome proliferatoractivated receptor- activators improve insulin action in muscle and adipose tissue ( 1316 ) with some reduction in hepatic glucose production ( 17 ) . They also seem to exert favorable effects on cardiovascular risk factors , including blood pressure , high-density lipoprotein cholesterol level , and triglyceride level , and on the proinflammatory and prothrombotic vascular environment in patients with type 2 diabetes ( 1315 ) . However , TZD therapy is associated with an increased risk for fluid retention and worsening of heart failure and often results in weight gain ( 18 , 19 ) . Exenatide therapy in combination with the commonly used glucose-lowering agentsmetformin or a sulfonylure aim proves glucose control in patients with type 2 diabetes ( 2022 ) . Both exenatide and TZDs regulate glucose levels through several mechanisms . These unique and potentially complementary mechanisms target the primary pathophysiologic defects that lead to hyperglycemia of type 2 diabetes , namely progressive -cell dysfunction and insulin resistance . In this context , our study compares the glycemic and body weight effects of exenatide versus placebo in patients with type 2 diabetes with suboptimal glycemic control who are receiving a background therapy of TZD or TZD plus metformin .  Methods Design Overview All patients participated in a 2-week , single-blind , placebo lead-in period , during which placebo was administered as twice-daily subcutaneous injections into the abdomen . After the placebo lead-in period , patients self-administered exenatide or placebo by subcutaneous injection into the abdomen within 15 minutes before the morning and evening meals . Exenatide-treated patients received fixed 5-g doses twice daily for 4 weeks , followed by 10-g doses twice daily for 12 weeks . The dosages of TZD and metformin were constant throughout the study . Lifestyle interventions were not included in the study protocol . The institutional review board approved a common clinical protocol for each site that was in accordance with the principles described in the Declaration of Helsinki ( 23 ) . All participants gave informed written consent before participation . The trial was conducted from May 2004 to August 2005 . Setting and Participants Forty-nine research clinics , hospitals , and primary care facilities in Canada , Spain , and the United States participated . Site investigators recruited patients through local investigators ' practice s and advertising . Patients were 21 to 75 years of age and were treated with a stable dosage of a TZD ( rosiglitazone , 4 mg/d , or pioglitazone , 30 mg/d ) for at least 4 months before screening . Patients received TZD therapy alone or in combination with a stable dosage of metformin ( no minimum dosage required ) for 30 days . Other inclusion criteria were a hemoglobin A1c value between 7.1 % and 10.0 % at screening , body mass index greater than 25 kg/m2 but less than 45 kg/m2 , and a history of stable body weight ( 10 % variation ) for at least 3 months before screening . R and omization and Interventions Within 3 weeks after screening , patients who met the inclusion criteria were r and omly assigned ( with equal probability ) to receive exenatide or placebo according to a central r and omization table . The sponsor ( Eli Lilly and Company , Indianapolis , Indiana ) generated the central r and omization table , and an automated , interactive voice-response system administered the assignments . R and omization was concealed and stratified by investigative site and current treatment ( TZD alone or TZD plus metformin ) . Prefilled disposable injection pens or cartridges containing indistinguishable exenatide and placebo solutions ( packaged central ly by Eli Lilly and Company ) were used . Outcomes and Measurements We measured hemoglobin A1c at screening , r and omization ( baseline or week 0 ) , and week 16 ( or , if possible , at the time of early discontinuation ) . We assessed fasting serum glucose concentrations at weeks 0 and 16 ( or at early discontinuation ) and measured body weight each month . We collected profiles of 7-point , self-monitored blood glucose levels ( measured before the morning , midday , and evening meals ; 2 hours after the start of each meal ; and at bedtime ) at weeks 0 , 4 , 8 , 12 , and 16 . We determined homeostasis model assessment ( HOMA ) of -cell function and insulin sensitivity , estimates of the contributions of -cell dysfunction and insulin resistance to hyperglycemia ( 24 ) , at weeks 0 and 16 ( or at early discontinuation ) . We measured plasma antiexenatide antibody levels at week 0 and the final visit . Adverse Events and Follow-up We assessed blood chemistries for safety monitoring at screening and week 16 ( or at early discontinuation ) . At monthly visits , we examined patients for pedal edema and asked them to report any adverse events . We classified adverse events according to the Medical Dictionary for Regulatory Activities . Study centers provided patients with study diaries , glucose monitors , and instructions for their use . Patients were encouraged to check their glucose levels when signs or symptoms of hypoglycemia ( including sweating , shaking , palpitations , or confusion ) occurred . In the diaries , patients recorded illnesses , concomitant medications , any changes to their antidiabetic oral medications ( TZDs or metformin ) , hypoglycemic episodes , glucose monitor readings , associated hypoglycemic symptoms , and treatments for the hypoglycemic events . The diaries contained modules dedicated to hypoglycemic events and were review ed by investigative staff at each study visit . We defined hypoglycemia as an incident when a patient obtained a glucose monitor reading less than 3.4 mmol/L ( < 60 mg/dL ) or experienced symptoms of hypoglycemia . We defined severe hypoglycemia as an incident when a patient required the assistance of another person and either obtained a glucose monitor reading less than 2.8 mmol/L ( < 50 mg/dL ) or promptly recovered after carbohydrate intervention . We assessed the severity of each adverse event ( mild , moderate , or severe ) . We assessed concomitant therapy and co interventions at each visit , and we recorded any deviations from the prescribed dosage regimens . We did not collect specific data about treatment adherence . No patient crossovers occurred during the trial . Statistical Analysis The primary efficacy variable was the change in hemoglobin A1c level from baseline . We determined that a sample size of 103 patients per group was needed to provide 90 % power to detect a difference of 0.5 % between groups in change in hemoglobin A1c level . We determined this on the basis of an estimated 25 % dropout rate after r and omization and with a 2-sided t-test at a significance level of 0.05 , assuming a common SD of 1.1 % . We defined 2 cohorts for the analyses of the efficacy measures : an intention-to-treat sample of patients who were r and omly assigned to study medication and a per protocol sample of r and omly assigned patients who had no violations of the inclusion or exclusion criteria , met no discontinuation criteria , and either completed the trial or discontinued at the last visit and had at least 16 weeks of exposure to study medication . The primary efficacy analysis of change in hemoglobin A1c level used a likelihood-based mixed-effects model analysis . The model included change in hemoglobin A1c level as the dependent variable ; treatment , week of visit , treatment-by-week interaction , baseline hemoglobin A1c level , TZD stratum , and pooled investigator ( sites with < 5 r and omly assigned patients with 1 postbaseline measure were pooled with another site or sites within the same country ) as fixed effects ; and patient and error as r and om effects . We included only patients with a baseline measure and at least 1 postbaseline value in the mixed-effects model analysis . We included all postbaseline measurements of change in hemoglobin A1c level in the analysis , including unscheduled measurements or measurements from patients who discontinued early . We did not impute missing data in the analysis . The mixed-effects model analysis assumed that the missing data were missing at r and om ( 25 ) . We examined week 16 for inferential purpose s only , because week 16 was the scheduled week for hemoglobin A1c measurement . We used compound 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 There is an explosive growth of type 2 diabetes mellitus ( T2DM ) in South Korea . According to Korea National Health and Nutritional Examination Survey performed in 2011 , the prevalence of diabetes among the population of 30 years and old is 12.4 % , and the number of patients with T2DM is expected to reach 6 million by 2050 [ 1 ] . Through studies such as UK Prospect i ve Diabetes Study , it has been well established that aggressive glycemic control in patients with newly diagnosed T2DM reduces microvascular and macrovascular complications of the disease [ 2 ] . Therefore , it is important to diagnose and treat T2DM in early phase . Several institutions have suggested target glycemic goals -for instance , American Diabetes Association ( ADA ) has recommended glycated hemoglobin ( HbA1c ) to be controlled below 7 % and stated that it should be maintained as close to normal level as possible in patients with short duration of T2DM , long life expectancy , and no cardiovascular disease [ 3,4 ] . Korean Diabetes Association ( KDA ) has recommended HbA1c below 6.5 % as target glycemic goal [ 5 ] . In general , a regimen of single oral hypoglycemic agent reduces HbA1c by approximately 1.5 % ; therefore , a combination therapy is recommended as initial management in HbA1c greater than 8 % [ 3 - 7 ] . The benefits of early combination therapy includes reduced glucotoxicity to β-cells through early normalization of blood glucose , reduced exposure time to hyperglycemia , and simultaneous blocking of multiple pathophysiology of T2DM [ 5,6 ] . The treatment guideline provided by ADA and European Association for the Study of Diabetes ( EASD ) , as well as that by KDA , recommends metformin in addition to lifestyle modification in patients with newly diagnosed T2DM as long as there are no contraindications [ 3 - 5 ] . In the past , addition of oral hypoglycemic agents with different mechanism of action or insulin was indicated after failure of metformin monotherapy ; however , since the recent recognition of importance of early aggressive glycemic control , metformin-based combination therapy has been widely employed in patients with HbA1c greater than 7.5 % to 8 % [ 3 - 6 ] . However , if combination of oral agents other than metformin is determined to be more effective based on several studies , an appropriate combination may be tailored to each patient depending not only on the mechanism , efficacy , side effect , and drug-drug interaction of each agent but also on individual lifestyle [ 3,6 ] . The major classes of hypoglycemic agents that may be combined with metformin include sulfonylurea ( SU ) , thiazolidinedion ( TZD ) , dipeptidyl-peptidase-4 inhibitor ( DPP4-i ) , insulin , and glucagon-like peptide-1 ( GLP-1 ) receptor agonist [ 6 ] . There is no clear guideline on the most effective combination regimen available for uncontrolled T2DM , and few studies investigated the effect of metformin-based early combination therapy . SU acts on β-cells of the pancreas as an insulin secretagogue-it is the most commonly used drug in conjunction with metformin [ 5,7 ] . One study evaluated the efficacy and safety of glyburide/metformin combination regimen as initial therapy in drug-naive T2DM patients over 2 years . The mean HbA1c at baseline and at 104 weeks after treatment was 8.4 % and 6.8 % , respectively . Combination with SU result ed in good glycemic control , but a significant increase in body weight and hypoglycemic episodes was noted [ 8 ] . While second generation SU ( e.g. , gliclazide , glimepiride ) report lower incidence of hypoglycemic episodes compared to long acting SU ( glyburide ) , it still needs to be taken into account in elderly patients [ 9 ] . In addition , another problem has been raised by a study entitled " A diabetes outcome progression trial (ADOPT)"-SU , when used as monotherapy agent , shows higher secondary failure rate compared to metformin or TZD [ 10 ] . Nonetheless , whether a similar result is observed when combined with metformin has not been reported as of yet . Pioglitazone , a peroxisomal proliferator-activated receptor γ agonist , reduces insulin resistance in the liver and peripheral tissues , leading to increases in suppression of hepatic glucose production and glucose uptake in peripheral tissues [ 6,7 ] . One cohort follow-up study compared and analyzed the results of initial combination therapy consisting of metformin and pioglitazone and initial sequential monotherapy of metformin and pioglitazone in T2DM patients with HbA1c greater than 7 % . This study found that initial combination therapy of metformin and pioglitazone was more effective than sequential combination therapy of metformin and pioglitazone in reaching and maintaining glycemic control , especially in subjects with HbA1c greater than 9 % [ 11 ] . Although pioglitazone  reduces the risk of death , myocardial infa rct ion , and stroke , there is potential weight gain , and its long-term use is associated with elevated risk of other side effects , such as bone fracture [ 12,13 ] . DPP4 inhibits DPP4 , an enzyme that de grade s incretin hormone GLP-1 , result ing in hypoglycemic effect [ 6,14 ] . Its combination with metformin is the subject of numerous recent studies . Lim et al. [ 15 ] reported a decrease in mean HbA1c of approximately 1.5 % in drug-naive Korean T2DM patients who initially underwent 52 weeks of combination therapy with metformin and stagliptin-this  efficacy was found to be greater in those with higher initial HbA1c after adjusting for BMI , insulin resistance , and other factors . In addition , it has suggested that DPP4-i may offer assistance in subjects with low β-cell function [ 15 ] . A series of recent studies have reported a combination regimen of metformin and DPP4-i to be associated with effective and safe glycemic control with no weight gain and low risk of hypoglycemia [ 16 - 18 ] . Nonetheless , there is a lack of studies on the effects of long-term DPP4-i use on cardiovascular disease , cancer , or the pancreas . The study by Lee et al. [ 19 ] was design ed to evaluate the efficacy of glycemic control in drug-naive or newly detected Korean T2DM patients receiving metformin-based dual combination therapy with SU , pioglitazone , or DPP4-i  , and they found similar hypoglycemic efficacy among SU , pioglitazone , and sitagliptin after 24 weeks of treatment in newly diagnosed T2DM subjects : this efficacy was similar or superior to that reported by other studies that combined SU , TZD , or DPP4-i to metformin [ 8,11,15 - 17 ] . Several studies have investigated which medications are more effective in Korean subjects [ 15,20,21 ] . In a study that reported more frequent  β-cell dysfunction  in Asian population compared to Westerners , combination therapy with SU could be effective in Korean [ 20 ] . DPP4-i was reported to be more effective in Asians than in Western [ 21 ] ; however , in another study that included diabetes in early stages , TZD demonstrated equal hypoglycemic efficacy when compared to SU [ 22 ] . These findings imply that it is difficult to label a specific drug as superior to others . Furthermore , patients with relatively high HbA1c at baseline responded well to combination oral hypoglycemic agent therapy [ 19 ] . Insulin therapy is the recommended treatment of choice in patients with HbA1c greater than 10 % to 11 % or with symptoms of hyperglycemia [ 3 - 6 ] ; however , in this study , dual therapy was initiated in subjects with HbA1c greater than 11 % . These patients showed a mean HbA1c below 6.5 % after 24 weeks of treatment , demonstrating that oral hypoglycemic agents can achieve adequate glycemic control within 24 weeks in early diabetic patients with severe hyperglycemia [ 19 ] . As the authors have stated , this maybe be due to relatively spared pancreatic β-cell function , as well as due to lower insulin resistance compared to study groups of other research es . The 2013 ADA/EASD guideline also recommended that glycemic target and control should be tailored to individuals [ 3 ] . In this study by Lee et al. [ 19 ] , metformin-based dual therapies with SU , TZD , and DPP4-i all showed similar efficacy . This suggests that the choice of oral hypoglycemic agents should be based on side effects , compliance , cost , and other factors rather than relying on a specific class of drug . Nonetheless , the analysis included only 24 weeks of data since the initial diagnosis , requiring further studies that evaluates not only the continued hypoglycemic efficacy of the combination therapy but also its side effects and its preventative effect on complications . A special attention should be paid in the future to the incidence of cardiovascular diseases and hypoglycemia in SU group , fracture and edema in TZD group , and pancreatitis , neoplasm , and cardiovascular disease in DPP4-i group 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 OBJECTIVE To determine the effect of thiazolidinedione treatment on sub clinical atherosclerosis progression in insulin-requiring patients with clinical characteristics suggesting type 2 diabetes . RESEARCH DESIGN AND METHODS Eligible participants ( n = 299 ) were r and omized within strata of baseline common carotid artery ( CCA ) intima-media thickness ( IMT ) ( < 0.8 mm , > or=0.8 mm ) to 400 mg troglitazone daily or placebo for 2 years . A general linear mixed-effects model was used to compare the rate of change in CCA-IMT between treatment groups . RESULTS Overall , average rates of CCA-IMT change were not significantly different between troglitazone- and placebo-treated subjects ( 0.0030 + /- 0.021 vs. 0.0066 + /- 0.021 mm/year ; P = 0.17 ) . In the stratum of subjects with CCA-IMT > or=0.8 mm , troglitazone significantly reduced the progression of CCA-IMT relative to placebo ( 0.0013 + /- 0.022 vs. 0.0084 + /- 0.023 mm/year ; P = 0.03 ) . Fasting glucose , insulin , and HbA(1c ) were significantly lower in troglitazone- versus placebo-treated subjects ( P < 0.01 ) . Whereas blood pressure significantly differed between treatment groups in the > or=0.8-mm stratum , there was no difference between treatment groups in the < 0.8-mm stratum . CONCLUSIONS Insulin sensitization and reduction in blood pressure may be contributory mechanisms by which troglitazone reduced sub clinical atherosclerosis progression in this cohort of well-controlled insulin-dependent patients with clinical characteristics suggesting type 2 diabetes OBJECTIVES We sought to assess the effect of rosiglitazone on markers of endothelial cell activation and acute-phase reactants in non-diabetic patients with coronary artery disease ( CAD ) . BACKGROUND Inflammation plays a key role in all stages of atherosclerosis and in the genesis of acute coronary syndromes . Rosiglitazone , a peroxisome proliferator-activated receptor gamma agonist , is used in the treatment of type 2 diabetes mellitus , and previous data suggest that it may have anti-inflammatory effects on atherosclerosis . METHODS Patients with stable , angiographically documented CAD without diabetes mellitus were investigated . Patients were r and omized in a double-blind manner to receive treatment with placebo or rosiglitazone ( 4 mg/day for 8 weeks followed by 8 mg/day for 4 weeks ) for 12 weeks . Eighty-four patients completed the study .  Fasting glucose , insulin , lipid profile , markers of endothelial activation , and inflammatory markers were measured at baseline and after 12 weeks . RESULTS Rosiglitazone treatment result ed in a significant reduction in E-selectin ( p = 0.03 ) , von Willebr and factor ( p = 0.007 ) , C-reactive protein ( p < 0.001 ) , fibrinogen ( p = 0.003 ) and the homeostasis model of insulin resistance index ( p = 0.02 ) , compared with placebo . Significant elevations in low-density lipoprotein and triglyceride levels were observed in the rosiglitazone group ( p < 0.01 ) . Within the rosiglitazone-treated group , reductions in C-reactive protein and von Willebr and factor were significantly correlated with a reduction in insulin resistance . CONCLUSIONS Rosiglitazone significantly reduces markers of endothelial cell activation and levels of acute-phase reactants in CAD patients without diabetes . Potential underlying mechanisms include insulin sensitization and direct modification of transcription within the vessel wall 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 CONTEXT Glucagon-like peptide-1 ( GLP-1 ) and GLP-1 receptor agonists provide beneficial cardiovascular effects by protecting against ischemia and reperfusion injury . Type 2 diabetes mellitus patients have reduced glycolysis in the heart . OBJECTIVE We hypothesized that cardioprotection by GLP-1 is achieved through increased glucose availability and utilization and aim ed to assess the effect of exenatide , a synthetic GLP-1 receptor agonist , on myocardial glucose uptake ( MGU ) , myocardial glucose transport , and myocardial blood flow ( MBF ) . DESIGN AND METHODS We conducted a r and omized , double-blinded , placebo-controlled crossover study in eight male , insulin-naive , type 2 diabetes mellitus patients without coronary artery disease .  Positron emission tomography was used to determine the effect of exenatide on MGU and MBF during a pituitary-pancreatic hyperglycemic clamp with (18)F-fluorodeoxyglucose and (13)N-ammonia as tracers . RESULTS Overall , exenatide did not alter MGU . However , regression analysis revealed that exenatide altered initial clearance of glucose over the membrane of cardiomyocytes and MGU , depending on the level of insulin resistance ( P = 0.017 and 0.010 , respectively ) . Exenatide increased MBF from 0.73 ± 0.094 to 0.85 ± 0.091 ml/g · min ( P = 0.0056 ) . Except for an increase in C-peptide levels , no differences in circulating hormones or metabolites were found . CONCLUSIONS The action of exenatide as an activator or inhibitor of the glucose transport and glucose uptake in cardiomyocytes is dependent on baseline activity of glucose transport and insulin resistance . Exenatide increases MBF without changing MGU 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 To investigate the influence of peroxisome proliferator-activated receptor-gamma ( PPAR-gamma ) gene variants on the response rate to therapy with the thiazolidinedione ( TZD ) pioglitazone , because in vitro studies have suggested that genetic variants of the PPAR-gamma gene may influence the drug efficacy of TZD . RESEARCH DESIGN AND METHODS A total of 131 patients were treated in an open-label , r and omized , multicenter study with pioglitazone ( 45 mg o.d . ) during a course of > or=26 weeks . Response to the pioglitazone therapy was defined by either a > 20 % decrease in fasting plasma glucose or a > 15 % decrease in HbA(1c ) values after 26 weeks of pioglitazone treatment . We evaluated the association between the PPAR-gamma genotype and the response rate to pioglitazone treatment . RESULTS The Pro12Ala and the Pro12Pro variants in the PPAR-gamma gene are not associated with the response rate to pioglitazone treatment in patients with type 2 diabetes . However , we identified initial fasting plasma glucose level > 11.0 mmol/l , HbA(1c ) value > 9.0 % , BMI > 32 kg/m(2 ) , and fasting C-peptide concentrations at baseline > 2.5 pmol/l as predominant confounding factors for the responder frequency to pioglitazone treatment . CONCLUSIONS The Pro12Ala variant in the PPAR-gamma gene does not affect the therapy efficacy of pioglitazone , suggesting that the drug-treatment response is independent from pharmacogenetic effects between PPAR-gamma and its lig and pioglitazone . Whether the Ala12Ala genotype plays a role in the response rate to TZD therapy remains to be determined Chronic hyperglycemia impairs insulin action , result ing in glucotoxicity , which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors . Here , we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 ( SGLT2 ) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes . Eighteen diabetic men were r and omized to receive either dapagliflozin ( n = 12 ) or placebo ( n = 6 ) for 2 weeks . We measured insulin-mediated whole body glucose uptake and endogenous glucose production ( EGP ) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique . Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose . Insulin-mediated tissue glucose disposal increased by approximately 18 % after 2 weeks of dapagliflozin treatment , while placebo-treated subjects had no change in insulin sensitivity . Surprisingly , following dapagliflozin treatment , EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration . Together , our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity . However , glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP . These results provide support for the glucotoxicity hypothesis , which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes A primary defect in the vascular action of insulin may be a key intermediate mechanism that links endothelial dysfunction with reduced insulin-mediated cellular glucose uptake in metabolic and cardiovascular disorders . The present study was design ed to characterize more fully the relations between insulin action and endothelial function in male patients with essential hypertension ( H , n=9 ) or type 2 diabetes ( D , n=9 ) along with healthy control subjects ( C ) matched for age , body mass index , and lipid profile . They attended for measurement of whole-body insulin sensitivity ( MCR ) by the hyperinsulinemic clamp technique ( day 1 ) and forearm vasoreactivity in response to intra-arterial infusions of insulin/glucose ( day 2 ) and N(G)-monomethyl-L-arginine ( L-NMMA ) and norepinephrine ( day 3 ) by bilateral venous-occlusion plethysmography . Results expressed as mean+/-SE MCR ( mL/kg per minute ) were 7.22+/-0 . 99 ( C ) , 6.32+/-0.78 ( H ) , and 5.06+/-0.53 ( D ) .  Insulin/glucose-mediated vasodilation ( IGMV ) was 17.1+/-5.6 % ( C ) , 17 . 2+/-5.5 % ( H ) , and 12.3+/-6.4 % ( D ) . L-NMMA vasoconstriction ( LNV ) was 37.9+/-5.1 % ( C ) , 37.5+/-2.3 % ( H ) , and 33.6+/-2.8 % ( D ) . There were no significant differences among groups for these parameters . Pooled correlation analyses revealed associations between MCR and IGMV ( r=0 . 46 , P<0.05 ) , MCR and LNV ( r=0.44 , P<0.05 ) , and IGMV and LNV ( r=0.52 , P<0.01 ) . This study supports functional coupling between insulin action ( both metabolic and vascular ) and basal endothelial nitric oxide production in humans Women with polycystic ovary syndrome ( PCOS ) are insulin resistant secondary to a postbinding defect in insulin signaling . Sequential euglycemic glucose clamp studies at 40 and 400 mU. m(-2 ) . min(-1 ) insulin doses with serial skeletal muscle biopsies were performed in PCOS and age- , weight- , and ethnicity-matched control women .  Steady-state insulin levels did not differ , but insulin-mediated glucose disposal was significantly decreased in PCOS women ( P < 0.05 ) . Insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase ( PI 3 K ) activity was significantly decreased in PCOS ( n = 12 ) compared with control skeletal muscle ( n = 8 ; P < 0.05 ) . There was no significant difference in the abundance of IR , IRS-1 , or the p85 regulatory subunit of PI 3 K in PCOS ( n = 14 ) compared with control ( n = 12 ) muscle . The abundance of IRS-2 was significantly increased ( P < 0.05 ) in PCOS skeletal muscle , suggesting a compensatory change . We conclude that there is a physiologically relevant defect in insulin receptor signaling in PCOS that is independent of obesity and type 2 diabetes mellitus 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 Strength training represents an alternative to endurance training for patients with type 2 diabetes . Little is known about the effect on insulin action and key proteins in skeletal muscle , and the necessary volume of strength training is unknown . A total of 10 type 2 diabetic subjects and 7 healthy men ( control subjects )  strength-trained one leg three times per week for 6 weeks while the other leg remained untrained . Each session lasted no more than 30 min . After strength training , muscle biopsies were obtained , and an isoglycemic-hyperinsulinemic clamp combined with arterio-femoral venous catheterization of both legs was carried out . In general , qualitatively similar responses were obtained in both groups . During the clamp , leg blood flow was higher ( P < 0.05 ) in trained versus untrained legs , but despite this , arterio-venous extraction glucose did not decrease in trained legs . Thus , leg glucose clearance was increased in trained legs ( P < 0.05 ) and more than explained by increases in muscle mass . Strength training increased protein content of GLUT4 , insulin receptor , protein kinase B-alpha/beta , glycogen synthase ( GS ) , and GS total activity . In conclusion , we found that strength training for 30 min three times per week increases insulin action in skeletal muscle in both groups . The adaptation is attributable to local contraction-mediated mechanisms involving key proteins in the insulin signaling cascade 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
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 .