OBJECTIVE -Recent studies have demonstrated that the treatment with thiazolidinediones reduces in-stent restenosis. The aim of this study was to elucidate the mechanism of the efficacy of pioglitazone for preventing in-stent restenosis in type 2 diabetic patients.RESEARCH DESIGN AND METHODS -We conducted a prospective, randomized trial involving 54 type 2 diabetic patients referred for coronary stenting who were randomly assigned to either the control or the pioglitazone group. Quantitative coronary angiography was performed at study entry and at 6 months follow-up. Endothelial nitric oxide synthase (eNOS), tumor necrosis factor ␣, interleukin-6, leptin, and adiponectin were measured at study entry and at 6 months follow-up.RESULTS -A total of 28 patients were randomly assigned to the control group, and 26 patients were assigned to the pioglitazone group. There were no significant differences in glycemic control levels or in lipid levels in the two groups at baseline or at follow-up. Insulin, homeostasis model assessment of insulin resistance, eNOS, and leptin at follow-up were significantly reduced in the pioglitazone group compared with the control group. The late luminal loss and in-stent restenosis were significantly less in the pioglitazone group than in the control group. Leptin independently correlated with late luminal loss at multiple regression analysis.CONCLUSIONS -The treatment with pioglitazone in type 2 diabetic patients significantly reduced leptin. This decreased leptin improved insulin resistance and endothelial function with the reduction of insulin. The improved endothelial function affected the reduction of in-stent restenosis. Diabetes Care 29:101-106, 2006I t has been reported that hyperinsulinemia is an independent risk factor for ischemic heart disease (1) and induces greater vascular smooth muscle cell proliferation in experimental models (2,3). Insulin resistance with hyperinsulinemia is associated with hypertension, glucose intolerance, obesity, and dyslipoproteinemias of low HDL cholesterol levels or hypertriglyceridemias, which are wellknown risk factors for coronary artery disease (4 -6).Recent studies showed that insulin resistance is an independent predictor of early restenosis after coronary stenting (7) and is associated with an increased incidence of myocardial infarction and death (8). Takagi and colleagues (9,10) demonstrated that troglitazone reduces neointimal tissue proliferation after coronary stent implantation, but pioglitazone does not reduce in-stent restenosis significantly. Donghoon et al. (11) showed that treatment with rosiglitazone significantly reduces in-stent restenosis. The efficacy of the thiazolidinediones (TZDs), which are novel insulin-sensitizing agents, against in-stent restenosis remains controversial.Endothelialization and endothelial function play an important role in coronary artery disease. Endothelial dysfunction has been considered a key element in the development of atherosclerosis and has also been found to be associated with insulin resistanc...

Insulin deficiency at early stages causes defects of mitochondrial function detectable in situ in cardiomyocytes. This suggests the possibility that such alterations are causative factors in the development of diabetic cardiomyopathy.

Diabetes mellitus is associated with alterations in lipid metabolism and cardiac dysfunction despite an absence of coronary arteriosclerotic changes. To investigate mechanisms of cardiac dysfunction in diabetic cardiomyopathy, we studied the relation between activities of membrane-bound enzymes and surrounding phospholipids in rats with diabetes induced with a single intravenous injection of streptozotocin (65 mg/kg). We found that total phospholipid content of sarcoplasmic reticulum membrane increased significantly 8 weeks after treatment with streptozotocin owing to increases in phosphatidylcholine and phosphatidylethanolamine, a decrease in arachidonic acid, and an increase in docosahexaenoic acid in the early stage of diabetes. Sarcolemmal Na+/K(+)-ATPase activity and the number of receptors decreased in isolated cardiomyocytes of diabetic rats 8 weeks after streptozotocin administration. The Ca2+ uptake of both sarcoplasmic reticulum and mitochondria decreased simultaneously in permeabilized, isolated cardiomyocytes from diabetic rats. The depression of membrane-bound enzyme activities was correlated with alterations in phospholipids, which are closely related to the microenvironment of membrane-bound enzymes and influence intracellular Ca2+ metabolism. Because these changes in phospholipids and fatty acids were reversible with insulin therapy, they are diabetes-specific and might be a cause of cardiac dysfunction in diabetes.

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