OBJECTIVE: We examined the relationship between glycemic control, vascular reactivity, and inflammation in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: Thirty subjects with type 2 diabetes were initiated on intensive insulin therapy (continuous subcutaneous insulin infusion [n = 12] or multiple daily injections [n = 18]) and then randomized to either pioglitazone (PIO group;45 mg/day), ramipril (RAM group; 10 mg/day), or placebo (PLC group) for 36 weeks. Euglycemic-hyperinsulinemic clamp was used to quantify insulin resistance, and plethysmography was used to assess changes in forearm blood flow (FBF) after 1) 5 min of reactive hyperemia and 2) brachial artery infusion of acetylcholine (7.5, 15, and 30 microg/min) and sodium nitroprusside (3 and 10 microg/min). RESULTS: The decreases in A1C (approximately 9.0-7.0%) and fasting plasma glucose (approximately 190-128 mg/dl) were equal in all groups. In the PIO group, glucose disposal increased from 3.1 to 4.7 mg x kg(-1) x min(-1), and there was a greater decrease in plasma triglycerides ( approximately 148 vs. 123 mg/dl) and free fatty acids (approximately 838 vs. 595 mEq/l) compared with the RAM or PLC groups (P < 0.05). Plasma adiponectin doubled with pioglitazone treatment (6.2 +/- 0.7 to 13.1 +/- 1.8 microg/ml), while endothelin-1 decreased only with ramipril treatment (2.5 +/- 0.2 to 1.1 +/- 0.2 pg/ml) (P < 001). The increase in FBF during reactive hyperemia (215%) and acetylcholine (from 132 to 205%, 216 to 262%, and 222 to 323%) was greater in the PIO versus RAM or PLC groups. In contrast, FBF during sodium nitroprusside treatment was greater in the RAM group (141-221% and 218-336%) compared with the PIO or PLC groups (all P < 0.05). CONCLUSIONS: Addition of pioglitazone or ramipril to intensive insulin therapy in type 2 diabetes further improves vascular dysfunction. Pioglitazone enhances endothelial-mediated vasodilation, whereas ACE inhibition enhances endothelial-independent vasodilation. These different vascular effects, combined with the observation that pioglitazone decreases free fatty acids and triglycerides and increases adiponectin, while ramipril reduces endothelin-1, suggest that different mechanisms underlie the vascular responses.