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Addition of Pioglitazone and Ramipril to Intensive Insulin Therapy in Type 2 Diabetic Patients Improves Vascular Dysfunction by Different Mechanisms

From the Texas Diabetes Institute, San Antonio, Texas

Address correspondence and reprint requests to Eugenio Cersosimo, MD, PhD, Mail Code 7886, 7703 Floyd Curl Dr., San Antonio, Texas 78229-3900. E-mail: eugenio.cersosimo{at}uhs-sa.com

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.

Abbreviations: ARB, angiotensin II receptor blockade • CSII, continuous subcutaneous insulin infusion • FBF, forearm blood flow • hsCRP, high-sensitivity C-reactive protein • IL, interleukin • MDII, multiple daily insulin injection • TZD, thiazolidinedione

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