Context: Vascular dysfunction and insulin resistance precede atherosclerosis in type 2 diabetes (T2DM). Better knowledge of the interaction between these is of considerable clinical interest.

Objective: To examine the association between inflammation, glucose and lipid metabolism and vascular dysfunction.

Design: Randomized double-blind controlled trial of pioglitazone vs. placebo other therapies aimed at equal glycemic control for 24 weeks

Study Setting: An academic tertiary referral clinic.

Patients and Interventions: Mexican American subjects with T2DM and no complications were randomly assigned to pioglitazone 45 mg daily (PIO, n=16) or placebo (CON, n=15) and matched for age, gender, BMI, diabetes duration and glycemic control. All subjects completed the study.

Main Outcome Measure: Improved vascular reactivity independent of glycemic control but closely related to plasma adiponectin, lipids and insulin sensitivity.

Results: After 24 weeks, there was an equal decrease in FPG (135 mg/dL), HbA_1c (7.0%) and glucose production (15%). FFA decrease (30% vs. 10%) and glucose disposal increase (40% vs. 25%) were greater in PIO vs. CON (p<0.05). In PIO, plasma HDL rose by 15% (p<0.05), and LDL & HDL particles size rose significantly (p<0.01). Plasma adiponectin doubled in PIO (from 6.1±0.8 to 12.7±2.1 µg/ml). Forearm blood flow (FBF) rose equally (130%) during reactive hyperemia in both groups, though after therapy, the increase was greater (p<0.001) in PIO (153%) than in CON (137%); vasodilation (Ach) was greater (p=0.01) in PIO (92%, 160% 204%) than in CON (74%, 130%, 144%) with Ach, and (PIO=164% & 253% vs. 116% & 230%, p=0.04) with SNP. The elevation in diameter was also greater in PIO (13% vs. 10%, p<0.05). Vascular responses correlated with plasma FFA, adiponectin and LDL particle size, but not with glycemic control.

Conclusion: These data indicate that pioglitazone improves vascular reactivity irrespective of glycemic control, and suggest a close association with changes in fat cell metabolism.