Relationship between vascular reactivity and lipids in Mexican-Americans with type 2 diabetes treated with pioglitazone.

Abstract

Vascular dysfunction and insulin resistance precede atherosclerosis in type 2 diabetes (T2DM). Better knowledge of the interaction between these is of considerable clinical interest. The objective of this study was to examine the association between inflammation, glucose, and lipid metabolism and vascular dysfunction. We conducted a randomized, double-blind, controlled trial of pioglitazone vs. placebo and other therapies aimed at equal glycemic control for 24 wk at an academic tertiary referral clinic. 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, body mass index, diabetes duration, and glycemic control. All subjects completed the study. We looked for improved vascular reactivity independent of glycemic control but closely related to plasma adiponectin, lipids, and insulin sensitivity. After 24 wk, there was an equal decrease in fasting plasma glucose (approximately 135 mg/dl), glycosylated hemoglobin (approximately 7.0%), and glucose production (approximately 15%). The decrease in free fatty acids (30 vs. 10%) and increase in glucose disposal (40 vs. 25%) were greater in PIO vs. CON (P<0.05). In PIO, plasma high-density lipoprotein rose by 15% (P<0.05), and low-density lipoprotein and high-density lipoprotein particle size rose significantly (P<0.01). Plasma adiponectin doubled in PIO (from 6.1+/-0.8 to 12.7+/-2.1 microg/ml). Forearm blood flow rose equally (approximately 130%) during reactive hyperemia in both groups, although after therapy, the increase was greater (P<0.001) in PIO (153%) than in CON (137%); vasodilation was greater (P=0.01) in PIO (92, 160, and 204%) than in CON with acetylcholine (74, 130, and 144%) and with sodium nitroprusside (PIO=164 and 253% vs. 116 and 230%; P=0.04). The elevation in diameter was also greater in PIO (13 vs. 10%; P<0.05). Vascular responses correlated with plasma free fatty acids, adiponectin, and low-density lipoprotein particle size but not with glycemic control. These data indicate that pioglitazone improves vascular reactivity irrespective of glycemic control and suggest a close association with changes in fat cell metabolism.