Peroxisome proliferator-activated receptor-gamma (PPAR gamma) plays a critical role in peripheral glucose homeostasis and energy metabolism, and inhibits cardiac hypertrophy in non-diabetic animal models. The functional role of PPAR gamma in the diabetic heart, however, is not fully understood. Therefore, we analyzed cardiac gene expression, metabolic control, and cardiac glucose uptake in male Zucker diabetic fatty rats (ZDF fa/fa) and lean ZDF rats (+/+) treated with the high affinity PPAR gamma agonist pioglitazone or placebo from 12 to 24 weeks of age. Hyperglycemia, hyperinsulinemia, and hypertriglyceridemia as well as lower cardiac PPAR gamma, glucose transporter-4 and alpha-myosin heavy chain expression levels were detected in diabetic ZDF rats compared to lean animals. Pioglitazone increased body weight and improved metabolic control, cardiac PPAR gamma, glut-4, and alpha-MHC expression levels in diabetic ZDF rats. Cardiac [F-18]fluorodeoxyglucose uptake was not detectable by micro-PET studies in untreated and pioglitazone treated ZDF fa/fa rats but was observed after administration of insulin to pioglitazone treated ZDF fa/fa rats. PPAR gamma agonists favorably affect cardiac gene expression in type-2 diabetic rats via activation and up-regulation of cardiac PPAR gamma expression whereas improvement of impaired cardiac glucose uptake in advanced type-2 diabetes requires co-administration of insulin. (c) 2005 Elsevier Inc. All rights reserved.