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.).
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"Treatment with TZDs is associated with an amelioration of proinflammatory adipokines and an increase in the secretion of adiponectin by adipocytes , restoring the response of adipose tissue to insulin action, as well as at the level of the liver and skeletal tissue . 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 , 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 . "
"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. "
"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 . 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]. "