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. 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. Improvement of cardiovascular risk markers by pioglitazone is independent from glycemic control: results from the pioneer study. Effects of Pioglitazone for Secondary Stroke Prevention in Patients with Impaired Glucose Tolerance and Newly Diagnosed Diabetes: The J-SPIRIT Study. Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. Long-term effects of pioglitazone in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Exercise training augments the peripheral insulin-sensitizing effects of pioglitazone in HIV-infected adults with insulin resistance and central adiposity. Effects of the dual peroxisome proliferator-activated receptor activator aleglitazar in patients with Type 2 Diabetes mellitus or prediabetes. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes. Lack of an effect of pioglitazone or glipizide on lipoprotein-associated phospholipase A2 in type 2 diabetes. Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. Effects of the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with Type 2 diabetes. Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Beneficial effect of pioglitazone on the outcome of catheter ablation in patients with paroxysmal atrial fibrillation and type 2 diabetes mellitus. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. PPAR-γ2 and PTPRD gene polymorphisms influence type 2 diabetes patients' response to pioglitazone in China Telmisartan but Not Candesartan Affects Adiponectin Expression In Vivo and In Vitro Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: rationale and design of the Insulin Resistance Intervention after Stroke Trial. Enhancement of insulin-stimulated myocardial glucose uptake in patients with Type 2 diabetes treated with rosiglitazone.
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 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 OBJECTIVES This study was performed to assess whether the anti-inflammatory and antiatherogenic effects of pioglitazone suggested by animal experiments are reproducible in man and independent from improvements in metabolic control . BACKGROUND Type 2 diabetes is associated with increased cardiovascular risk . METHODS A total of 192 patients were enrolled into a six-month , prospect i ve , open-label , controlled clinical study . They were r and omized to receive either pioglitazone ( 45 mg ) or glimepiride ( 1 to 6 mg , with the intent to optimize therapy ) . Biochemical and clinical markers to assess therapeutic effects included HbA1c , fasting glucose , insulin , adiponectin , lipids , high-sensitivity C-reactive protein ( hsCRP ) , intracellular adhesion molecule , vascular cell adhesion molecule , vascular endothelial growth factor , fibrinogen , von Willebr and factor , matrix metalloproteinase (MMP)-9 , monocyte chemoattractant protein (MCP)-1 , soluble CD40 lig and , and carotid intima-media thickness ( IMT ) . RESULTS The study was completed by 173 patients ( 66 female , 107 male ; age [ + /- SD ] : 63 + /- 8 years ; disease duration : 7.2 + /- 7.2 years ; HbA1c : 7.5 + /- 0.9 % ; pioglitazone arm : 89 patients ) . A comparable reduction in HbA1c was seen in both groups ( p < 0.001 ) . In the pioglitazone group , reductions were observed for glucose ( p < 0.001 vs. glimepiride group at end point ) , insulin ( p < 0.001 ) , low-density lipoprotein/high-density lipoprotein ratio ( p < 0.001 ) , hsCRP ( p < 0.05 ) , MMP-9 ( p < 0.05 ) , MCP-1 ( p < 0.05 ) , and carotid IMT ( p < 0.001 ) , and an increase was seen in high-density lipoprotein ( p < 0.001 ) and adiponectin ( p < 0.001 ) . Spearman ranks analysis revealed only one correlation between the reduction in cardiovascular risk parameters and the improvement in the metabolic parameters ( MMP-9 and fasting blood glucose , p < 0.05 ) CONCLUSIONS This prospect i ve study gives evidence of an anti-inflammatory and antiatherogenic effect of pioglitazone versus glimepiride . This effect is independent from blood glucose control and may be attributed to peroxisome proliferator-activated receptor gamma activation AIM Prediabetes is an independent risk factor for future stroke . However , no effective treatment has yet been established for the recurrence of stroke in patients with prediabetes . Here we investigated the effects of pioglitazone , a potent peroxisome proliferator-activated receptor-gamma agonist , for the reduction of recurrent stroke in patients with prediabetes . METHODS Participants were patients who had a symptomatic ischemic stroke or transient ischemic attack ( TIA ) without a history of type 2 diabetes mellitus and who were diagnosed to have IGT or newly diagnosed diabetes by a 75-g oral glucose tolerance test . These patients were r and omized to either receive or not receive pioglitazone . The primary endpoint was a recurrence of ischemic stroke . RESULTS A total of 120 patients were enrolled in the study . Sixty-three patients received pioglitazone and 57 were enrolled in the control group that did not receive pioglitazone . The majority of patients ( 68.3 % ) were prescribed 15 mg of pioglitazone , while the remaining patients ( 31.7 % ) were treated with 30 mg of pioglitazone . Over a median follow-up period of 2.8 years , treatment with pioglitazone was found to be associated with a lower rate of the primary endpoint ( recurrence of stroke ) than that observed in the control group [ event rate=4.8 % pioglitazone vs 10.5 % control , hazard ratio=0.62 , 95 % confidence interval 0.13 - 2.35 , p=0.49 ] . However , differences were not statistically significant . CONCLUSIONS While this study was too underpowered to determine the effect of pioglitazone , the result failed to show beneficial effects in patients of ischemic stroke or TIA with impaired glucose tolerance and newly diagnosed diabetes There have been increasing evidence s that thiazolidinediones , peroxisome proliferator-activated receptor gamma ( PPARgamma ) agonists , may have some antiatherogenic actions . We have previously reported that troglitazone has a potent inhibitory effect on common carotid arterial intima-media thickness ( IMT ) in subjects with type 2 diabetes . However , some studies suggested a possibility that PPARgamma activators may have protoatherogenic actions , raising concern about their detrimental effects in diabetic subjects . In the present study , we investigated the effect of treatment with pioglitazone , another PPARgamma agonist , on IMT in a total of 106 Japanese subjects with type 2 diabetes .  Pioglitazone ( 30 mg daily ) was administered for 6 months in 53 patients . Compared to control group ( n = 53 ) , the group given pioglitazone showed a significant decrease in IMT as early as 3 months after the administration . The decrease in IMT was also found after 6 months ( IMT change : -0.084[SE 0.023 ] mm vs. control 0.022[SE 0.006 ] mm , P < 0.001 ) , although the difference between those after 3 and 6 months did not reach any statistical significance . These findings indicate that thiazolidinediones cause an inhibition of early atherosclerotic process PPARgamma activation Abstract Objective : To evaluate the efficacy of pioglitazone for the prevention of macrovascular outcomes in Japanese patients with type 2 diabetes , without a recent history of macrovascular morbidity . Research design and methods : This 2.5–4 year , prospect i ve , r and omized , open-label , blinded-endpoint study was conducted in 20 Japanese centers . Patients received pioglitazone ± other oral glucose-lowering drugs ( excluding another thiazolidinedione ) [ n = 293 ] or oral glucose-lowering drugs excluding thiazolidinediones ( n = 294 ) . Treatment was adjusted to achieve HbA1c < 6.5 % . The primary endpoint was the time to onset of a macrovascular event . Results : Pioglitazone delayed the time to onset of macrovascular events and was associated with a lower cumulative incidence of such events ( 3.56 % vs. 4.49 % for controls ) . Neither finding achieved statistical significance . This was likely because of the type of patient included in the study ( i.e. no recent history of cardiovascular events ) and the high use of concomitant anti-diabetic agents . Reductions in HbA1c , fasting blood glucose and fasting blood insulin levels , and an increase in HDL-C were significantly greater with pioglitazone throughout most of the study ( p < 0.05 ) . Fewer patients in the pioglitazone group commenced permanent treatment with insulin ( 3.3 % vs. 13.7 % in the control group ) . Adverse events were reported by 97.6 % of the pioglitazone group and 96.9 % of the control group ( serious adverse events , including deaths , were 20.1 vs. 22.2 % , respectively ) . The only notable difference between the two groups was a higher incidence of edema in the pioglitazone group . The main limitation of this study was that too few patients were included to identify statistically significant differences in the primary endpoint . Conclusions : Pioglitazone produced good glycemic control in Japanese patients with type 2 diabetes , and significantly fewer patients treated with pioglitazone needed long-term insulin therapy . These changes were associated with a trend towards delayed onset of macrovascular events . Clinical trial registration : UMIN000001363 OBJECTIVE The PROspect i ve pioglitAzone Clinical Trial In macroVascular Events ( PROactive ) assesses the effect of pioglitazone , a peroxisome proliferator-activated receptor agonist , with anti-inflammatory and vascular properties , on the secondary prevention of macrovascular events in type 2 diabetes . RESEARCH DESIGN AND METHODS PROactive is an on-going r and omized , double-blind outcome study in patients with type 2 diabetes managed with diet and /or oral blood glucose-lowering drugs (  combination of oral agents with insulin is permitted ) who have a history of macrovascular disease . Patients are r and omized to receive pioglitazone ( forced titration from 15 to 30 to 45 mg , depending on tolerability ) or placebo in addition to existing therapy . The primary end point is the time from r and omization to occurrence of a new macrovascular event or death . Follow-up is estimated to span 4 years . RESULTS A total of 5238 patients have been r and omized from 19 countries . At entry into the study , patients enrolled are a mean age of 61.8 years , with type 2 diabetes for a mean of 9.5 years ; 60.9 and 61.5 % are taking metformin or a sulfonylurea , respectively ; and 33.6 % are using insulin in addition to oral glucose-lowering drugs . The majority of patients are men ( 66.1 % ) . Patients are required to meet one or more of entry criteria , as follows : > 6 months ' history of myocardial infa rct ion ( 46.7 % ) ; coronary artery revascularization ( 30.8 % ) , stroke ( 18.8 % ) , or acute coronary syndrome for > 3 months ( 13.7 % ) ; other evidence of coronary artery disease ( 48.1 % ) ; or peripheral arterial occlusive disease ( 19.9 % ) . One-half ( 48.5 % ) of the patients have two or more of these risk factors . Three-quarters ( 75.4 % ) have hypertension  , and 58.8 % are current or previous  smokers . CONCLUSIONS The cohort of patients enrolled in PROactive is a typical type 2 diabetic population at high risk of further macrovascular events . The characteristics of this population are ideal for assessing the ability of pioglitazone to reduce the cardiovascular risk of patients with type 2 diabetes The prevalence and incidence of insulin resistance and type 2 diabetes mellitus ( DM ) are higher in people treated for human immunodeficiency virus-1 ( HIV ) infection than in the general population . Identifying safe and effective interventions is a high priority . We evaluated whether the peroxisome proliferator-activated receptor-γ agonist pioglitazone with exercise training improves central and peripheral insulin sensitivity more than pioglitazone alone in HIV-infected adults with insulin resistance and central adiposity . Forty-four HIV-infected adults with baseline insulin resistance and central adiposity were r and omly assigned to 4 mo of pioglitazone ( 30 mg/day ) with or without supervised , progressive aerobic , and resistance exercise training ( 1.5 - 2 h/day , 3 days/wk ) . The hyperinsulinemic euglycemic clamp was used to evaluate alterations in central and peripheral insulin sensitivity . Thirty-nine participants completed the study . Hepatic insulin sensitivity improved similarly in both groups . Exercise training augmented the beneficial effects of pioglitazone on peripheral insulin sensitivity . Greater improvements in peripheral insulin sensitivity were associated with reductions in total body and limb adipose content rather than increases in limb adiposity or pioglitazone-induced increases in adiponectin concentration . We conclude that supplementing pioglitazone with increased physical activity improved insulin sensitivity more effectively than pioglitazone alone in HIV-infected adults with insulin resistance and central adiposity . Pioglitazone alone did not significantly increase limb adipose content . Potential cardiovascular benefits of these interventions in HIV need investigation 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 BACKGROUND No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis , which is characterized by insulin resistance , steatosis , and necroinflammation with or without centrilobular fibrosis . Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus . METHODS We r and omly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy-confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet  ( a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight ) plus pioglitazone ( 45 mg daily ) or a hypocaloric diet plus placebo . Before and after treatment , we assessed hepatic histologic features , hepatic fat content by means of magnetic resonance spectroscopy , and glucose turnover during an oral glucose tolerance test ( [14C]glucose given with the oral glucose load and [3H]glucose given by intravenous infusion ) . RESULTS Diet plus pioglitazone , as compared with diet plus placebo , improved glycemic control and glucose tolerance ( P<0.001 ) , normalized liver aminotransferase levels as it decreased plasma aspartate aminotransferase levels ( by 40 % vs. 21 % , P=0.04 ) , decreased alanine aminotransferase levels ( by 58 % vs. 34 % , P<0.001 ) , decreased hepatic fat content ( by 54 % vs. 0 % , P<0.001 ) , and increased hepatic insulin sensitivity ( by 48 % vs. 14 % , P=0.008 ) . Administration of pioglitazone , as compared with placebo , was associated with improvement in histologic findings with regard to steatosis ( P=0.003 ) , ballooning necrosis ( P=0.02 ) , and inflammation ( P=0.008 ) . Subjects in the pioglitazone group had a greater reduction in necroinflammation ( 85 % vs. 38 % , P=0.001 ) , but the reduction in fibrosis did not differ significantly from that in the placebo group ( P=0.08 ) . Fatigue and mild lower-extremity edema developed in one subject who received pioglitazone ; no other adverse events were observed . CONCLUSIONS In this proof-of-concept study , the administration of pioglitazone led to metabolic and histologic improvement in subjects with nonalcoholic steatohepatitis . Larger controlled trials of longer duration are warranted to assess the long-term clinical benefit of pioglitazone . ( Clinical Trials.gov number , NCT00227110 [ Clinical Trials.gov ] . ) Pioglitazone , a thiazolidinedione , improves glycemic control primarily by increasing peripheral insulin sensitivity in patients with type 2 diabetes , whereas metformin , a biguanide , exerts its effect primarily by decreasing hepatic glucose output . In the first head-to-head , double-blind clinical trial comparing these two oral antihyperglycemic medications ( OAMs ) , we studied the effect of 32-wk monotherapy on glycemic control and insulin sensitivity in 205 patients with recently diagnosed type 2 diabetes who were naive to OAM therapy . Subjects were r and omized to either 30 mg pioglitazone or 850 mg metformin daily with titrations upward to 45 mg ( 77 % of pioglitazone patients ) and 2550 mg ( 73 % of metformin patients ) , as indicated , to achieve fasting plasma glucose levels of less than 7.0 mmol/liter ( 126 mg/dl ) . Pioglitazone was comparable to metformin in improving glycemic control as measured by hemoglobin A1C and fasting plasma glucose . At endpoint , pioglitazone was significantly more effective than metformin in improving indicators of insulin sensitivity , as determined by reduction of fasting serum insulin ( P = 0.003 ) and by analysis of homeostasis model assessment for insulin sensitivity ( HOMA-S ; P = 0.002 ) . Both OAM therapies were well tolerated . Therefore , pioglitazone and metformin are equally efficacious in regard to glycemic control , but they exert significantly different effects on insulin sensitivity due to differing mechanisms of action . The more pronounced improvement in indicators of insulin sensitivity by pioglitazone , as compared with metformin monotherapy in patients recently diagnosed with type 2 diabetes who are OAM-naive , may be of interest for further clinical evaluation OBJECTIVE To study the effects of pioglitazone , a peroxisome proliferator-activated receptor-y agonist with vascular beneficial effects , and glipizide , an insulin secretagogue , on novel inflammatory vascular risk markers in subjects with and without type 2 diabetes . METHODS We studied 11 subjects without diabetes and 19 matched subjects with diabetes . The subjects with diabetes were r and omly assigned to receive either 45 mg daily of pioglitazone ( N = 8) or 10 mg daily of glipizide ( N = 11 ) ( median dose ) for 12 weeks . Lipoprotein-associated phospholipase A2 ( LpPLA2 ) , vascular cell adhesion molecule ( VCAM-1 ) , intracellular adhesion molecule ( ICAM-1 ) , and e-selectin were measured by established techniques before and after therapy with either agent . The subjects without diabetes were studied only once . RESULTS The study subjects with diabetes had higher ( P<0.05 ) LpPLA2 , e-selectin , and VCAM-1 levels than did those without diabetes . ICAM-1 levels tended to be higher ( P = 0.07 ) in the study subjects with than in those without diabetes . Neither pioglitazone nor glipizide therapy significantly altered LpPLA2 or VCAM-1 concentrations . While pioglitazone therapy reduced ( P<0.05 ) eselectin concentrations , glipizide therapy reduced ( P<0.03 ) ICAM-1 concentrations . CONCLUSION Type 2 diabetes is associated with elevated concentrations of the novel vascular risk marker LpPLA2 and inflammatory risk markers e-selectin and VCAM-1 . Neither pioglitazone nor glipizide significantly altered LpPLA2 , VCAM-1 , or highly sensitive C-reactive protein levels after 12 weeks of therapy . In study subjects with type 2 diabetes , e-selectin concentrations declined significantly with pioglitazone therapy , whereas ICAM-1 concentrations decreased significantly with glipizide therapy Polycystic ovary syndrome ( PCOS ) is characterized by hyper and rogenism , chronic anovulation , and insulin resistance ; long-term consequences include diabetes mellitus type 2 . The aim of this r and omized , double-blind , controlled trial was to investigate whether the thiazolidinedione derivative pioglitazone diminishes insulin resistance and hyper and rogenism and enhances ovulation rates in women with PCOS . Forty premenopausal women with PCOS were r and omly allocated to treatment with either pioglitazone ( 30 mg/d ) or placebo for periods of 3 months . Administration of pioglitazone result ed in a remarkable decline in both fasting serum insulin levels ( P < 0.02 ) and the area under the insulin response curve after an oral glucose load ( P < 0.02 ) . This represented an increase in insulin sensitivity and a decrease in insulin secretion ( P < 0.05 ) . Furthermore , pioglitazone increased serum SHBG ( P < 0.05 ) , result ing in a significant decrease in the free and rogen index ( P < 0.05 compared with placebo ) . Treatment with pioglitazone was also associated with higher ovulation rates ( P < 0.02 ) . Thus , pioglitazone significantly improved insulin sensitivity , hyper and rogenism , and ovulation rates in women with PCOS , thereby providing both metabolic and reproductive benefits Aims /hypothesisGlitazones are powerful insulin sensitisers prescribed for the treatment of type 2 diabetes . Their use is , however , associated with fluid retention and an increased risk of congestive heart failure . We previously demonstrated that pioglitazone increases proximal sodium reabsorption in healthy volunteers . This study examines the effects of pioglitazone on renal sodium h and ling in individuals prone to insulin resistance , i.e. those with diabetes and /or hypertension . Methods In this double-blind r and omised placebo-controlled four-way crossover study , we examined the effects of pioglitazone ( 45 mg daily during 6 weeks ) or placebo on renal , systemic and hormonal responses to changes in sodium intake in 16 individuals , eight with type 2 diabetes and eight with hypertension . Results Pioglitazone was associated with a rapid increase in body weight and an increase in diurnal proximal sodium reabsorption , without any change in renal haemodynamics or in the modulation of the renin – angiotensin aldosterone system to changes in salt intake . A compensatory increase in brain natriuretic peptide levels was observed . In spite of sodium retention , pioglitazone dissociated the blood-pressure response to salt and abolished salt sensitivity in salt-sensitive individuals . Conclusions /interpretationPioglitazone increases diurnal proximal sodium retention in diabetic and hypertensive individuals . These effects cause fluid retention and may contribute to the increased incidence of congestive heart failure with glitazones . Trial registration : Clinical Trial.gov NCT01090752 Funding : Hypertension Research Foundation BACKGROUND Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infa rct ion and stroke . There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma ( PPAR gamma ) could reduce macrovascular complications . Our aim , therefore , was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes . METHODS We did a prospect i ve , r and omised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease .  We recruited patients from primary -care practice s and hospitals . We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg ( n=2605 ) or matching placebo ( n=2633 ) , to be taken in addition to their glucose-lowering drugs and other medications . Our primary endpoint was the composite of all-cause mortality , non fatal myocardial infa rct ion ( including silent myocardial infa rct ion ) , stroke , acute coronary syndrome , endovascular or surgical intervention in the coronary or leg arteries , and amputation above the ankle . Analysis was by intention to treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N NCT00174993 . FINDINGS Two patients were lost to follow-up , but were included in analyses . The average time of observation was 34.5 months . 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint ( HR 0.90 , 95 % CI 0.80 - 1.02 , p=0.095 ) . The main secondary endpoint was the composite of all-cause mortality , non-fatal myocardial infa rct ion , and stroke . 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint ( 0.84 , 0.72 - 0.98 , p=0.027 ) . Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified . 6 % ( 149 of 2065 ) and 4 % ( 108 of 2633 ) of those in the pioglitazone and placebo groups , respectively , were admitted to hospital with heart failure ; mortality rates from heart failure did not differ between groups . INTERPRETATION Pioglitazone reduces the composite of all-cause mortality , non-fatal myocardial infa rct ion , and stroke in patients with type 2 diabetes who have a high risk of macrovascular events AIMS This study compared the effects of 52 weeks ' treatment with pioglitazone , a thiazolidinedione that reduces insulin resistance , and glibenclamide , on insulin sensitivity , glycaemic control , and lipids in patients with Type 2 diabetes . METHODS Patients with Type 2 diabetes were r and omized to receive either pioglitazone ( initially 30 mg QD , n = 91 ) or micronized glibenclamide ( initially 1.75 mg QD , n = 109 ) as monotherapy . Doses were titrated ( to 45 mg for pioglitazone and 10.5 mg for glibenclamide ) to achieve glycaemic targets during the next 12 weeks : fasting blood glucose of < or = 7 mmol/l and 1-h postpr and ial blood glucose of < or = 10 mmol/l . Patients were maintained on the titrated dose for 40 weeks . RESULTS Pioglitazone significantly increased insulin sensitivity compared with glibenclamide , as assessed by homeostasis model assessment ( 17.0 % vs. -13.0 % ; P < 0.001 ) , quantitative insulin sensitivity check index ( 0.011 vs. -0.007 ; P < 0.001 ) and fasting serum insulin ( -1.3 pmol/l vs. 23.8 pmol/l ; P = 0.007 ) . The glibenclamide group had significantly lower HbA1c than the pioglitazone group after 12 weeks of therapy ( 7.8 % vs. 8.3 % , P = 0.015 ) , but significantly higher HbA1c after 52 weeks of therapy ( 7.8 % vs. 7.2 % , P = 0.001 ) . Pioglitazone significantly ( vs. glibenclamide ) increased mean HDL-C ( P < 0.001 ) , decreased mean triglycerides ( P = 0.019 ) , and decreased mean atherogenic index of plasma ( AIP ; P = 0.001 ) and mean total cholesterol/HDL-C ( P = 0.004 ) , without significantly elevating mean total cholesterol or mean LDL-C compared with glibenclamide . CONCLUSIONS These data suggest that the effects of pioglitazone are more sustained than those of glibenclamide for improving insulin sensitivity in patients with Type 2 diabetes , and that 52 weeks ' treatment with pioglitazone has favourable effects on glycaemic control and lipoprotein profile 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 AIMS Pioglitazone , one of the peroxisome proliferator-activated receptor-gamma activators , possesses anti-inflammatory and antioxidant properties . In the present study , we sought to identify the impact of pioglitazone on the outcome of catheter ablation for paroxysmal atrial fibrillation ( PAF ) . METHODS AND RESULTS We conducted a prospect i ve observational cohort study of 150 consecutive patients undergoing catheter ablation of drug-refractory PAF . All patients had a history of type 2 diabetes mellitus ( T2DM ) and were divided based on whether they received pioglitazone before ablation or not . After grouping , 51 patients treated with pioglitazone  and 99 control subjects were followed up at least 15 months after ablation . After a single ablation , sinus rhythm was maintained in 44 patients ( 86.3 % ) of the pioglitazone group vs. 70 patients ( 70.7 % ) of the control group ( P = 0.034 ) without antiarrhythmic drug during a mean follow-up of 22.9 ± 5.1 months . The second ablation was performed in 5 patients ( 9.8 % ) from the pioglitazone group and in 24 patients ( 24.2 % ) from the control group ( P = 0.034 ) . Multivariate logistic analysis showed left atrium diameter was associated with a high risk of atrial tachyarrhythmias recurrence , and treatment with renin-angiotensin system inhibitor as well as pioglitazone was associated with a reduced atrial tachyarrhythmias recurrence rate . CONCLUSION Pioglitazone improved the preservation of sinus rhythm and reduced the reablation rate in patients with PAF and T2DM after catheter ablation 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 Aim : To investigate the influence of peroxisome proliferator-activated receptor γ2 ( PPAR-γ2 ) gene polymorphism rs1801282 and protein tyrosine phosphatase receptor type D ( PTPRD ) gene polymorphism rs17584499 on the occurrence of type 2 diabetes and pioglitazone efficacy in a Chinese Han population . Methods : One hundred ninety seven type 2 diabetes patients and 212 healthy controls were enrolled . Among them , 67 type 2 diabetes patients were administered pioglitazone ( 30 mg/d , po ) for 3 months . All the subjects were genotyped for genetic variants in PPAR-γ2 and PTPRD using MALDI-TOF mass spectrometry  . Fasting plasma glucose , postpr and ial plasma glucose , glycated hemoglobin , serum triglyceride , total cholesterol , low-density and high-density lipoprotein-cholesterol were determined . Results : The PPAR-γ2 gene rs1801282 polymorphism was significantly associated with type 2 diabetes susceptibility ( OR=0.515 , 95 % CI 0.268–0.990 ) and the PTPRD gene rs17584499 polymorphism was also significantly associated with type 2 diabetes ( OR=1.984 , 95 % CI 1.135–3.469 ) in a dominant model adjusted for age , gender and BMI . After pioglitazone treatment for 3 months , the type 2 diabetes patients with PPAR-γ2 rs1801282 CG genotypes significantly showed higher differential values of postpr and ial plasma glucose and serum triglyceride compared with those with rs1801282 CC genotype . The patients with PTPRD rs17584499 CT+TT genotypes showed significantly lower differential value of postpr and ial plasma glucose compared to those with rs17584499 CC genotype . Conclusion : Diabetes risk alleles in PPAR-γ2 ( rs1801282 ) and PTPRD ( rs17584499 ) are associated with pioglitazone therapeutic efficacy To examine the effects of telmisartan on peroxisome proliferator – activated receptor γ activation , we compared the effects of telmisartan with those of c and esartan on adipocytokines and glucose and lipid metabolism in vivo and in vitro . In vivo , 56 patients with both type 2 diabetes and hypertension were enrolled and r and omized to receive either telmisartan ( 40 mg ) or c and esartan ( 8 mg ) for 3 months . Serum adiponectin , HbA1c levels , lipid profiles and blood pressure were recorded at the beginning and 3 months later . In vitro , differentiated 3T3-L1 adipocytes were treated with telmisartan , c and esartan , pioglitazone or vehicle for 24 h , and then adiponectin mRNA and protein levels were measured . The results showed that most of the metabolic parameters , including the lipid profiles , did not change significantly during the study in either group . However , the changes in serum adiponectin and plasma glucose over 3 months were significantly greater in the telmisartan group than in the c and esartan group . In vitro , although the protein level of adiponectin was not significantly elevated , the mRNA expression of adiponectin was elevated 1.5-fold by telmisartan in 3T3-L1 adipocytes . Our findings suggest that telmisartan may have beneficial effects in type 2 diabetes beyond its antihypertensive effect BACKGROUND Recurrent vascular events remain a major source of morbidity and mortality after stroke or transient ischemic attack ( TIA ) . The IRIS Trial is evaluating an approach to secondary prevention based on the established association between insulin resistance and increased risk for ischemic vascular events . Specifically , IRIS will test the effectiveness of pioglitazone , an insulin-sensitizing drug of the thiazolidinedione class , for reducing the risk for stroke and myocardial infa rct ion ( MI ) among insulin resistant , nondiabetic patients with a recent ischemic stroke or TIA . DESIGN Eligible patients for IRIS must have had insulin resistance defined by a Homeostasis Model Assessment -Insulin Resistance > 3.0 without meeting criteria for diabetes . Within 6 months of the index stroke or TIA , patients were r and omly assigned to pioglitazone ( titrated from 15 to 45 mg/d ) or matching placebo and followed for up to 5 years . The primary outcome is time to stroke or MI . Secondary outcomes include time to stroke alone , acute coronary syndrome , diabetes , cognitive decline , and all-cause mortality .  Enrollment of 3,876 participants from 179 sites in 7 countries was completed in January 2013 . Participant follow-up will continue until July 2015 . SUMMARY The IRIS Trial will determine whether treatment with pioglitazone improves cardiovascular outcomes of nondiabetic , insulin-resistant patients with stroke or TIA . Results are expected in early 2016 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
Further , in a cohort study of patients with type 2 diabetes , pioglitazone therapy was associated with a statistically significant decrease in the risk of all-cause mortality .
Despite these beneficial effects , the meta- analysis showed that pioglitazone therapy had higher risks of heart failure , bone fractures , edema and weight gain .
The low-dose pioglitazone therapy may show the same degree of improvements in glucose and lipid metabolism , fatty liver , insulin resistance , and adiponectin as the st and ard- and high-dose pioglitazone therapy .
Furthermore , the low-dose pioglitazone therapy may also show less adverse effects on weight gain , edema and heart failure as compared with the st and ard- and high-dose pioglitazone therapy
Pioglitazone is one of thiazolidinedione derivatives , which stimulates nuclear peroxisome proliferator-activated receptor gamma and improves glucose and lipid metabolism and insulin sensitivity .
A recent systematic review and meta- analysis showed that pioglitazone therapy was associated with a lower risk of major adverse cardiovascular events in patients with pre-diabetes and diabetes .