Article

Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance

Texas Diabetes Institute and University of Texas Health Science Center, San Antonio, TX 78229, USA.
New England Journal of Medicine (Impact Factor: 55.87). 03/2011; 364(12):1104-15. DOI: 10.1056/NEJMoa1010949
Source: PubMed
ABSTRACT
Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance.
We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing.
Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima-media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007).
As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).

Full-text preview

Available from: nejm.org
  • Source
    • "Treatment with TZDs is associated with an amelioration of proinflammatory adipokines and an increase in the secretion of adiponectin by adipocytes [50], restoring the response of adipose tissue to insulin action, as well as at the level of the liver and skeletal tissue [20]. Evidence for the long-term impact of these broad metabolic and antiinflammatory effects can be appreciated in the potential for pioglitazone to prevent the progression to T2DM in patients with impaired glucose tolerance, improving not only plasma glucose levels but also blood pressure and lipid levels [51], all factors that play an important role in the morbidity and mortality of patients with T2DM. Both pioglitazone and rosiglitazone have been tested in patients with NASH [47]. "
    Full-text · Article · Dec 2016
  • Source
    • "On the other hand, AMPK can be activated by exercises and calorie restriction, which have long been known to increase insulin sensitivity and decrease the prevalence of T2D (Knowler et al., 2002). In addition, pharmacological agents developed for the treatment of type 2 diabetes, such as metformin, TZDs, GLP1 agonists, and dipeptidyl peptidase IV (DPP IV) inhibitors, have all been shown to activate AMPK, and in several instances, have demonstrated utility in preventing the progression of impaired glucose tolerance to type 2 diabetes (DeFronzo et al., 2011; Knowler et al., 2002; LeBrasseur et al., 2006; Nawrocki et al., 2006; Svegliati‐Baroni et al., 2011; Viollet et al., 2012). So AMPK becomes an attractive target for treatment of T2D. "
    [Show abstract] [Hide abstract] ABSTRACT: Rhizoma Anemarrhenae has been used in Asian countries for thousands of years to treat diabetes. Insulin resistance (IR) is the primary cause responsible for type 2 diabetes. The aim of this study was to to assess the hypoglycemic and insulin sensitizing properties of Rhizoma Anemarrhenae extract (TFA) in animal models of insulin resistance and/or diabetes and to delineate modes of action. In-vivo studies were performed on STZ-induced diabetic mice and KK-Ay mice, the former of which were given the extract alone or in combination with insulin for 7 days, and the latter of which were given the extract for 8 consecutive weeks. Fasting blood glucose and serum insulin levels were measured. Pancreatic tissue sections were examined using transmission electron micrographs. Further, hyperinsulinemic-euglycemic clamping study was conducted in BCG vaccine-induced insulin resistance rats, and glucose infusion rate was examined. Mechanisms of action were investigated in 3T3-L1 and Hela cells using Western blot analysis. Our study showed that TFA enhanced the glucose-lowering effects of exogenous insulin administration in STZ-induced diabetic mice. Therapeutic administration of TFA significantly reduced fasting blood glucose, and serum insulin levels, and markedly increased the size and the number of insulin-producing beta cells in KK-Ay mice. Further, hyperinsulinemic-euglycemic clamping study showed that glucose infusion rate was significantly improved in TFA-treated BCG vaccine-induced insulin resistance rats. Study of mechanism of action revealed that TFA increased phosphorylation of AMPK and its downstream target, acetyl-CoA carboxylase (ACC) in 3T3-L1 cells. It activates AMPK in a LKB1-independent manner, providing a unified explanation for the beneficial effects of TFA. This study that TFA mediates activation of AMPK and improves overall glucose and lipid metabolism in diabetic rodents, highlights the potential utility of TFA for the management of type 2 diabetes. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.
    Full-text · Article · Jul 2015 · Journal of ethnopharmacology
  • Source
    • "Using bone marrow transplantation from angiotensin II receptor 1a (AT1a) deficient animals, we also showed that deletion of macrophage AT1a lessens uninephrectomy (UNx)-induced acceleration of atherosclerosis and alters macrophage phenotype distribution patterns in the lesions [12]. Peroxisome proliferator-activated receptor-g (PPARg) is a member of the ligand-activated nuclear receptor family with critical functions in energy balance and prominent atheroprotective effects [13,14]. Interestingly, PPARg has been shown to have a reciprocal relationship with RAS [15,16]. "
    [Show abstract] [Hide abstract] ABSTRACT: Chronic kidney disease (CKD) amplifies atherosclerosis, which involves renin-angiotensin system (RAS) regulation of macrophages. RAS influences peroxisome proliferator-activated receptor-γ (PPARγ), a modulator of atherogenic functions of macrophages, however, little is known about its effects in CKD. We examined the impact of combined therapy with a PPARγ agonist and angiotensin receptor blocker on atherogenesis in a murine uninephrectomy model. Apolipoprotein E knockout mice underwent uninephrectomy (UNx) and treatment with pioglitazone (UNx + Pio), losartan (UNx + Los), or both (UNx + Pio/Los) for 10 weeks. Extent and characteristics of atherosclerotic lesions and macrophage phenotypes were assessed; RAW264.7 and primary peritoneal mouse cells were used to examine pioglitazone and losartan effects on macrophage phenotype and inflammatory response. UNx significantly increased atherosclerosis. Pioglitazone and losartan each significantly reduced the atherosclerotic burden by 29.6% and 33.5%, respectively; although the benefit was dramatically augmented by combination treatment which lessened atherosclerosis by 55.7%. Assessment of plaques revealed significantly greater macrophage area in UNx + Pio/Los (80.7 ± 11.4% vs. 50.3 ± 4.2% in UNx + Pio and 57.2 ± 6.5% in UNx + Los) with more apoptotic cells. The expanded macrophage-rich lesions of UNx + Pio/Los had more alternatively activated, Ym-1 and arginine 1-positive M2 phenotypes (Ym-1: 33.6 ± 8.2%, p < 0.05 vs. 12.0 ± 1.1% in UNx; arginase 1: 27.8 ± 0.9%, p < 0.05 vs. 11.8 ± 1.3% in UNx). In vitro, pioglitazone alone and together with losartan was more effective than losartan alone in dampening lipopolysaccharide-induced cytokine production, suppressing M1 phenotypic change while enhancing M2 phenotypic change. Combination of pioglitazone and losartan is more effective in reducing renal injury-induced atherosclerosis than either treatment alone. This benefit reflects mitigation in macrophage cytokine production, enhanced apoptosis, and a shift toward an anti-inflammatory phenotype. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jul 2015 · Atherosclerosis
Show more