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
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
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 .