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 T2DM subjects

Study Design: Thirty subjects with T2DM 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, 45 mg/d), ramipril (RAM, 10 mg/d), or placebo (PLC) for 36 wks. Euglycemic hyperinsulinemic clamp was used to quatitfy insulin resistance and plethysmography to assess changes in forearm blood flow (FBF) after: (i) 5 min of reactive hyperemia (RH); (ii) brachial artery infusion of acetylcholine (Ach: 7.5,15,30 μg/min) and sodium nitroprusside (SNP: 3,10 μg/min)

Results: The decrease in HbA_1c (∼9.0 to 7.0%) and FPG (∼190 to 128 mg/dl) were equal in all groups. In PIO, glucose disposal increased from 3.1 to 4.7 mg/kg•min, and there was a greater decrease in plasma triglycerides (∼148 vs. 123 mg/dl) and FFA (∼838 vs. 595 mEq/L) vs. RAM or PLC (p<0.05). Plasma adiponectin doubled with PIO (6.2±0.7 to 13.1±1.8 μg/ml), while endothelin-1 decreased only with RAM (2.5±0.2 to 1.1±0.2 pg/ml, p<001). The increase in FBF during RH (215%) and Ach (from 132 to 205%, 216 to 262%, and 222 to 323%) was greater in PIO vs. RAM or PLC. In contrast, FBF during SNP was greater in RAM (141 to 221% and 218 to 336%) vs. PIO or PLC (all p<0.05).

Conclusion: Addition of PIO or RAM to intensive insulin therapy in T2DM further improves vascular dysfunction. PIO enhances endothelial-mediated, whereas ACE inhibition enhances endothelial-independent vasodilation. These different vascular effects, combined with the observation that PIO decreases FFA and triglycerides and increases adiponectin, while RAM reduces endothelin-1, suggest that different mechanisms underlie the vascular responses.