Effect of a Peroxisome Proliferator–Activated Receptor-γ Agonist on Myocardial Blood Flow in Type 2 Diabetes

Abstract

OBJECTIVE -The relationship between coronary endothelial function and insulin resistance remains speculative. We sought to determine whether pioglitazone, an insulin-sensitizing peroxisome proliferator-activated receptor (PPAR)-␥ agonist, improves cardiac endothelial function in individuals with type 2 diabetes.RESEARCH DESIGN AND METHODS -Sixteen subjects with insulin-treated type 2 diabetes and without overt cardiovascular disease were randomly assigned to receive either 45 mg of pioglitazone or matching placebo for 3 months. Rest and adenosine-stimulated myocardial blood flow (MBF) were quantified with [13 N]ammonia and positron emission tomography at baseline and study conclusion.RESULTS -After 3 months, HbA 1c levels dropped by 0.68% in the pioglitazone group and increased by 0.17% in the placebo group (P ϭ 0.009 for difference between groups). Triglyceride (Ϫ93 vs. Ϫ39 mg/dl, P ϭ 0.026) and HDL concentrations (ϩ4.8 vs. Ϫ6.0 mg/dl, P ϭ 0.014) improved significantly in the pioglitazone group compared with placebo. Despite these favorable changes, there was no demonstrable change in baseline MBF (Ϫ0.05 Ϯ 0.24 vs. Ϫ0.09 Ϯ 0.24 ml ⅐ min Ϫ1 ⅐ g Ϫ1 , P ϭ 0.45), adenosine-stimulated MBF (0.10 Ϯ 0.75 vs. 0.14 Ϯ 0.31 ml ⅐ min Ϫ1⅐ g Ϫ1 , P ϭ 0.25), or coronary flow reserve (0.45 Ϯ 1.22 vs. 0.35 Ϯ 0.72 ml ⅐ min Ϫ1 ⅐ g Ϫ1 , P ϭ 0.64) after 12 weeks of exposure to pioglitazone or placebo, respectively. Regression analysis revealed that lower glucose concentration at the time of the study was associated with higher coronary flow reserve (P ϭ 0.012).CONCLUSIONS -Pioglitazone treatment for 12 weeks in subjects with insulin-requiring type 2 diabetes had no demonstrable effect on coronary flow reserve despite metabolic improvements. Higher ambient glucose levels contribute to impaired vascular reactivity in individuals with diabetes. Diabetes Care 28:1145-1150, 2005A therosclerotic vascular disease and its sequelae remain the primary causes of mortality in patients with diabetes, accounting for 65-75% of deaths (1). Recent attention has focused on functional abnormalities of the endothelium as an early step in the pathogenesis of diabetic heart disease (2,3). Notably, studies on individuals with diabetes have demonstrated a consistently higher myocardial blood flow (MBF) at rest and impaired myocardial vasodilation capacity (4).Endothelial dysfunction occurs when endogenous vasoconstrictors such as endothelin and angiotensin II dominate the action of naturally occurring vasodilators such as nitric oxide, an imbalance linked to known cardiovascular risk factors (5-7). Importantly, measures of endothelial dysfunction predict subsequent cardiovascular events (8). Insulin resistance has emerged as a putative common link between diabetes and endothelial dysfunction. Those with insulin resistance demonstrate impaired endothelial function (7,9) even before diabetes is diagnosed, and insulin induces vasodilation via endothelial nitric oxide release (10,11).Thiazolidinediones activate the nuclear receptor peroxisome proliferatoractiv...

Coronary Circulatory Function in Patients with the Metabolic Syndrome

“…Similar findings have been reported in the WIZARD study (11). Our findings suggest that the increased risk associated with the metabolic syndrome in high-risk individuals may be related to the effect of insulin resistance on atherosclerosis burden (32) rather than coronary microvascular function (33).…”

Pioglitazone Improves Myocardial Blood Flow and Glucose Utilization in Nondiabetic Patients With Combined Hyperlipidemia

“…This is contrary to the belief that hyperglycemia is a key modulator of vasodilator function, at least in patients with diabetes (17,41). The key could be the improved insulin sensitivity during treatment with pioglitazone, which might influence MBF directly.…”

“…treatment with pioglitazone or placebo. Despite favorable changes in glucose and lipid parameters in the pioglitazone group, the study did not demonstrate any significant change in resting and hyperemic MBF or CFR (17). In a nonrandomized study in 25 Mexican Americans with evidence of insulin resistance, 3 months' treatment with thiazolidinediones did not lead to significant changes in resting and dipyridamolestimulated MBF, although the MBF response to cold pressor test, which is a marker of endothelium dependent vasodilatation, was significantly improved (18).…”

“…Indeed, thiazolidinediones have been shown to have a favorable effect on some serum lipid parameters in patients with diabetes (11)(12)(13) and in nondiabetic patients with hypertension (14). Thiazolidinediones have been reported to improve endothelial function (15) and myocardial glucose utilization (MGU) (16,17) in patients with type 2 diabetes. However, treatment with pioglitazone had no effect on MBF in patients with insulin-treated type 2 diabetes (17), although thiazolidinediones did improve coronary vasomotor abnormalities in Mexican Americans with insulin resistance (18).…”

“…Thiazolidinediones have been reported to improve endothelial function (15) and myocardial glucose utilization (MGU) (16,17) in patients with type 2 diabetes. However, treatment with pioglitazone had no effect on MBF in patients with insulin-treated type 2 diabetes (17), although thiazolidinediones did improve coronary vasomotor abnormalities in Mexican Americans with insulin resistance (18).…”