Addition of pioglitazone and ramipril to intensive insulin therapy in type 2 diabetic patients improves vascular dysfunction by different mechanisms

Abstract

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 μg/min) and sodium nitroprusside (3 and 10 μg/min). RESULTS- The decreases in A1C (∼9.0-7.0%) and fasting plasma glucose (∼190-128 mg/dl) were equal in all groups. In the PIO group, glucose disposal increased from 3.1 to 4.7 mg · kg-1 · min-1, and there was a greater decrease in plasma triglycerides (∼148 vs. 123 mg/dl) and free fatty acids (∼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 μg/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. © 2008 by the American Diabetes Association.