Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations 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.
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PMID:Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. 1516 71

BACKGROUND: Ligands of the peroxisome proliferator-activated receptor-gamma (PPARgamma) induce apoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. Preclinical studies have shown that the thiazolidinedione pioglitazone, an FDA-approved PPARgamma agonist used to treat type 2 diabetes, delays the onset and reduces the severity of clinical symptoms in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). We therefore tested the safety and therapeutic potential of oral pioglitazone in a patient with secondary MS. CASE PRESENTATION: The rationale and risks of taking pioglitazone were carefully explained to the patient, consent was obtained, and treatment was initiated at 15 mg per day p.o. and then increased by 15 mg biweekly to 45 mg per day p.o. for the duration of the treatment. Safety was assessed by measurements of metabolic profiles, blood pressure, and edema; effects on clinical symptoms were assessed by measurement of cognition, motor function and strength, and MRI. Within 4 weeks the patient exhibited increased appetite, cognition and attention span. After 12 months treatment, body weight increased from 27.3 to 35.9 kg (32%) and maintained throughout the duration of the study. Upper extremity strength and coordination improved, and increased fine coordination was noted unilaterally after 8 months and bilaterally after 15 months. After 8 months therapy, the patient demonstrated improvement in orientation, short-term memory, and attention span. MRIs carried out after 10 and 18 months of treatment showed no perceptible change in overall brain atrophy, extent of demyelination, or in Gd-enhancement. After 3.0 years on pioglitazone, the patient continues to be clinically stable, with no adverse events. CONCLUSIONS: In a patient with secondary progressive MS, daily treatment with 45 mg p.o. pioglitazone for 3 years induced apparent clinical improvement without adverse events. Pioglitazone should therefore be considered for further testing of therapeutic potential in MS patients.
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PMID:Effect of pioglitazone treatment in a patient with secondary multiple sclerosis. 1528 99

Atherosclerosis is the major cause of morbidity and mortality in patients with type 2 diabetes, and pioglitazone has been reported to have anti-inflammatory and potential antiatherogenic effects. The aim of the present study was to determine whether pioglitazone, glibenclamide, or voglibose affects carotid intima-media thickness (IMT), pulse wave velocity (PWV), and urinary albumin excretion (UAE) in normotensive type 2 diabetic nephropathy patients. Forty-five normotensive type 2 diabetes patients with microalbuminuria were randomized to 12-month treatment with pioglitazone (30 mg/d, n = 15), glibenclamide (5 mg/d, n = 15), or voglibose (0.6 mg/d, n = 15). Pre- and posttreatment UAE, PWV, and IMT values were compared between treatment groups and a group of age-matched healthy control subjects (n = 30). Pretreatment PWV, IMT, and UAE values differed little between the 3 groups, but UAE was greater in the 45 type 2 diabetes patients (132.5 +/- 36.4 microg/min) than in the control subjects (6.2 +/- 1.8 microg/min, P < .001). IMT (0.76 +/- 0.12 mm) was significantly greater in the diabetics than in the controls (0.60 +/- 0.08 mm, P < .01). PWV (1,840 +/- 320 cm/s) was also significantly greater in the diabetics than in the controls (1,350 +/- 225 cm/s, P < .01). After 6 and 12 months, UAE, IMT, and PWV in the pioglitazone treatment group were significantly lower than those in the glibenclamide treatment group and voglibose treatment group (UAE: 6 months, P < .05 and 12 months, P < .01; IMT and PWV: 6 months, P < .05 and 12 months, P < .05). Pioglitazone, but not glibenclamide or voglibose, appears to be effective in reducing UAE, IMT, and PWV in normotensive type 2 diabetes patients with microalbuminuria.
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PMID:Effect of pioglitazone on carotid intima-media thickness and arterial stiffness in type 2 diabetic nephropathy patients. 1537 99

Decreased functional beta-cell mass in type 1 and type 2 diabetes is due to beta-cell apoptosis and impaired secretory function suggested to be mediated, in part, by immune- and/or high-glucose-induced production of IL-1beta acting through the nuclear factor kappaB (NFkappaB)/Fas pathway. The aim of this study was to determine whether two drugs believed to block NFkappaB activation, the thiazolidinedione (glitazone) pioglitazone and the nonsteroidal antiinflammatory drug sodium salicylate, can protect human beta-cells against the toxic effects of IL-1beta and high glucose in vitro. Human islets were maintained in culture 2-4 d at 100 mg/dl (5.5 mm) glucose with or without (control) IL-1beta or at 600 mg/dl (33.3 mm) glucose. IL-1beta and 600 mg/dl glucose increased beta-cell apoptosis and abolished short-term glucose-stimulated insulin secretion. Both drugs protected partially against loss of glucose-stimulated insulin secretion and prevented completely increased apoptosis caused by IL-1beta or 600 mg/dl glucose. IL-1beta secretion from islets was increased by 4-d culture at 600 mg/dl, and this was blocked by pioglitazone. Both drugs prevented activation of beta-cell NFkappaB by high glucose. Pioglitazone and sodium salicylate thus protect human islets against the detrimental effects of IL-1beta and high glucose by blocking NFkappaB activation and may therefore be useful in retarding the manifestation and progression of diabetes.
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PMID:Pioglitazone and sodium salicylate protect human beta-cells against apoptosis and impaired function induced by glucose and interleukin-1beta. 1547 6

Pioglitazone increases the insulin sensitivity of peripheral tissues and may provide an alternative first-line treatment for type 2 diabetes. This study compared metabolic control in drug-naive type 2 diabetes patients given either pioglitazone or metformin. Eleven hundred and ninety-nine patients with poorly controlled type 2 diabetes mellitus [glycosylated hemoglobin (HbA1c), 7.5-11%; normal, 4.3-6.1%] were randomized to receive either pioglitazone (< or =45 mg/d) or metformin (< or =850 mg, three times daily). HbA1c, fasting plasma glucose (FPG), insulin levels, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol, triglycerides, free fatty acids, and urinary albumin/creatinine ratio were measured. Mean HbA1c decreased in both treatment groups from baseline to wk 52 (-1.4% and -1.5%). Significantly greater mean reductions in FPG were observed in the pioglitazone group (-45.0 mg/dl; -2.5 mmol/liter) than in the metformin (-39.6 mg/dl; -2.2 mmol/liter) group (P = 0.016). Favorable changes in triglycerides and HDL-C were more pronounced with pioglitazone. Although low density lipoprotein cholesterol and TC levels increased with pioglitazone, TC/HDL-C ratios decreased similarly with both treatments. The urinary albumin/creatinine ratio was reduced by 19% with pioglitazone treatment, but remained unchanged with metformin therapy (-1%; P = 0.002). There was an increase in body weight of 1.9 kg in the pioglitazone group and a decrease of 2.5 kg in the metformin group. The overall frequency of adverse events was similar between treatment groups, but adverse event profiles were different between treatment groups. HbA1c reduction is similar after pioglitazone and metformin monotherapies, but differences in FPG, plasma lipids, and adverse effects between the two compounds may influence decision-making in individual prescribers.
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PMID:Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. 1557 60

A total of 3,713 patients with poorly controlled type 2 diabetes were enroled into four multicentre, double-blind studies and randomised to receive pioglitazone, sulphonylurea, metformin or a combination of two of these agents for up to 52 weeks. Data from patients with a lipid evaluation, at week 52, were pooled, and treatment groups were compared using analysis of covariance. Pioglitazone, alone or combined with metformin or sulphonylurea, resulted in mean decreases in triglycerides (-9 to -11%), total/HDL cholesterol ratio (-9 to -10%) and free fatty acid (-0.051 to -0.123 mmol/l) and mean increases in HDL cholesterol (17 to 20%). The sustained, favourable effects of pioglitazone on important components of diabetic dyslipidaemia may contribute to reduced cardiovascular disease risk, among patients with type 2 diabetes.
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PMID:Effects of pioglitazone on the components of diabetic dyslipidaemia: results of double-blind, multicentre, randomised studies. 1558 67

Thiazolidinediones, such as pioglitazone, seem to exert direct antiatherosclerotic and antirestenotic effects on type 2 diabetes, in part due to an induction of vascular smooth muscle cell (VSMC) apoptosis. We aimed to study the role of transforming growth factor (TGF)-beta in rat aortic VSMC. Pioglitazone at 100 micromol/l increased apoptosis without affecting DNA synthesis, and this effect was reversed by an anti-TGF-beta1 antibody. Extracellular TGF-beta1 levels were rapidly increased after treatment with pioglitazone in a peroxisome proliferator-activated receptor (PPAR)-gamma-dependent mechanism because this secretion was blocked by the PPAR-gamma inhibitor GW9662. Pioglitazone subsequently increased the nuclear recruitment of phospho-Smad2, without any effect on protein expression. According to our results, we propose that the apoptotic effect of pioglitazone on VSMC depends on the following sequence: PPAR-gamma activation, TGF-beta1 release, and selective phospho-Smad2 nuclear recruitment. Management of Smad signaling on VSMC might provide future clinical benefits in vascular diseases.
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PMID:Pioglitazone induces vascular smooth muscle cell apoptosis through a peroxisome proliferator-activated receptor-gamma, transforming growth factor-beta1, and a Smad2-dependent mechanism. 1573 60

Pioglitazone is in the class of compounds known as the thiazolidinediones and is used to treat type 2 diabetes mellitus. The first in its class compound, troglitazone, was withdrawn from the U.S. market in 2000 due to a high incidence of hepatotoxicity and drug-induced liver failure. Reactive ring-opened products of troglitazone have been identified and evidence suggests that these reactive intermediates might be a potential cause of hepatotoxicity. The present work shows that pioglitazone has a reactive ring-opened product which was trapped by glutathione and positively identified by high performance liquid chromatography with tandem mass spectrometry accurate mass measurements. The novel thiazolidinedione ring-opened products of pioglitazone were identified in rat and human liver microsomes and in freshly isolated rat but not human hepatocytes.
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PMID:Metabolic activation of pioglitazone identified from rat and human liver microsomes and freshly isolated hepatocytes. 1576 18

Pioglitazone monotherapy and combinations were assessed in patients with type 2 diabetes and metabolic syndrome (Adult Treatment Panel III criteria) from four worldwide randomised, multicentre, double-blind studies. Patients were treated for 52 weeks with pioglitazone (PIO, n = 1040), sulphonylurea (SU, n = 535) or metformin (MET, n = 500) PIO + SU (n = 277) or MET + SU (n = 273); or PIO + MET (n = 286) or SU + MET (n = 275). Pooled week 52 glycaemic and lipid changes were compared using analysis of covariance. Haemoglobin A(1c) decreased significantly with pioglitazone compared with sulphonylurea (p < 0.05). Fasting, 2- and 3-h plasma glucose, insulin and homeostasis model assessment for insulin resistance decreased significantly with pioglitazone compared with other monotherapies (p < 0.05) and decreased significantly with PIO + MET compared with SU + MET (p < 0.05). Pioglitazone, alone and with metformin, improved lipid components of diabetic dyslipidaemia more than did their respective comparison groups. Pioglitazone was associated with weight increase. In conclusion, pioglitazone provided effective glycaemic control and lipid profile improvements in patients with type 2 diabetes and metabolic syndrome.
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PMID:Pioglitazone in a subgroup of patients with type 2 diabetes meeting the criteria for metabolic syndrome. 1585 87

Thiazolidenediones such as pioglitazone improve insulin sensitivity in diabetic patients by several mechanisms, including increased uptake and metabolism of free fatty acids in adipose tissue. The purpose of the present study was to determine the effect of pioglitazone on mitochondrial biogenesis and expression of genes involved in fatty acid oxidation in subcutaneous fat. Patients with type 2 diabetes were randomly divided into two groups and treated with placebo or pioglitazone (45 mg/day) for 12 weeks. Mitochondrial DNA copy number and expression of genes involved in mitochondrial biogenesis were quantified by real-time PCR. Pioglitazone treatment significantly increased mitochondrial copy number and expression of factors involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1alpha and mitochondrial transcription factor A. Treatment with pioglitazone stimulated the expression of genes in the fatty acid oxidation pathway, including carnitine palmitoyltransferase-1, malonyl-CoA decarboxylase, and medium-chain acyl-CoA dehydrogenase. The expression of PPAR-alpha, a transcriptional regulator of genes encoding mitochondrial enzymes involved in fatty acid oxidation, was higher after pioglitazone treatment. Finally, the increased mitochondrial copy number and the higher expression of genes involved in fatty acid oxidation in human adipocytes may contribute to the hypolipidemic effects of pioglitazone.
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PMID:Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. 1585 25


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