Effect of a peroxisome proliferator-activated receptor-gamma agonist on myocardial blood flow in type 2 diabetes.

ABSTRACT

OBJECTIVE: The relationship between coronary endothelial function and insulin resistance remains speculative. We sought to determine whether pioglitazone, an insulin-sensitizing peroxisome proliferator-activated receptor (PPAR)-gamma agonist, improves cardiac endothelial function in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Sixteen subjects with insulin-treated type 2 diabetes and without overt cardiovascular disease were randomly assigned to receive either 45 mg of pioglitazone or matching placebo for 3 months. Rest and adenosine-stimulated myocardial blood flow (MBF) were quantified with [(13)N]ammonia and positron emission tomography at baseline and study conclusion. RESULTS: After 3 months, HbA(1c) levels dropped by 0.68% in the pioglitazone group and increased by 0.17% in the placebo group (P = 0.009 for difference between groups). Triglyceride (-93 vs. -39 mg/dl, P = 0.026) and HDL concentrations (+4.8 vs. -6.0 mg/dl, P = 0.014) improved significantly in the pioglitazone group compared with placebo. Despite these favorable changes, there was no demonstrable change in baseline MBF (-0.05 +/- 0.24 vs. -0.09 +/- 0.24 ml . min(-1) . g(-1), P = 0.45), adenosine-stimulated MBF (0.10 +/- 0.75 vs. 0.14 +/- 0.31 ml . min(-1) . g(-1), P = 0.25), or coronary flow reserve (0.45 +/- 1.22 vs. 0.35 +/- 0.72 ml . min(-1) . g(-1), P = 0.64) after 12 weeks of exposure to pioglitazone or placebo, respectively. Regression analysis revealed that lower glucose concentration at the time of the study was associated with higher coronary flow reserve (P = 0.012). CONCLUSIONS: Pioglitazone treatment for 12 weeks in subjects with insulin-requiring type 2 diabetes had no demonstrable effect on coronary flow reserve despite metabolic improvements. Higher ambient glucose levels contribute to impaired vascular reactivity in individuals with diabetes.