Rosiglitazone Improves Myocardial Glucose Uptake in Patients With Type 2 Diabetes and Coronary Artery Disease

A 16-Week Randomized, Double-Blind, Placebo-Controlled Study

Riikka Lautamäki; K.E. Juhani Airaksinen; Marko Seppänen; Jyri Toikka; Matti Luotolahti; Elizabeth Ball; Ronald Borra; Risto Härkönen; Patricia Iozzo; Murray Stewart; Juhani Knuuti; Pirjo Nuutila


Diabetes. 2005;54(9):2787-2794. 

In This Article

Abstract and Introduction

Rosiglitazone therapy improves insulin sensitivity and glucose uptake in patients with uncomplicated type 2 diabetes. In coronary artery disease (CAD), glucose is an important source of energy and preserved myocardial glucose uptake is essential for the viability of jeopardized myocardium. The aim was to test whether rosiglitazone changes myocardial metabolism in type 2 diabetic patients with CAD. We studied 54 patients (38 men and 16 women) with type 2 diabetes (HbA1c 7.2 + 0.9%) and CAD. Myocardial glucose uptake was measured with [18F]fluoro-2-deoxy-D-glucose positron emission tomography in ischemic (evaluated by single-photon emission tomography and coronary angiography) and nonischemic regions during euglycemic-hyperinsulinemic clamp before and after a 16-week intervention period with rosiglitazone (n = 27) or placebo (n = 27). Rosiglitazone significantly improved glycemic control (P < 0.0001) and whole-body insulin sensitivity (P < 0.0001). Rosiglitazone increased myocardial glucose uptake from 20.6 ± 11.8 to 25.5 ± 12.4 µmol · 100 g-1 · min-1 (P = 0.038 vs. baseline, P = 0.023 vs. placebo) in ischemic regions and from 21.7 ± 12.1 to 28.0 ± 12.7 µmol · 100 g-1 · min-1 (P = 0.014 vs. baseline, P = 0.003 vs. placebo) in nonischemic regions. The increase in myocardial glucose uptake was partly explained by the suppression of free fatty acid levels during clamp. Rosiglitazone therapy significantly increased insulin sensitivity and improved myocardial glucose uptake in type 2 diabetic patients with CAD. These results suggest that rosiglitazone therapy may facilitate myocardial glucose storage and utilization in these patients.

The risk of myocardial infarction is increased in diabetes,[1] and the outcome is poor with these patients. It has been suggested that one reason might be abnormal myocardial substrate metabolism.[2] Myocardium is able to use free fatty acids (FFAs), glucose, lactate, pyruvate, and ketone bodies as energy sources. In healthy subjects, the primary sources of energy are FFAs at fast and glucose in the fed state.[3] In patients with ischemic heart disease, glucose becomes an important energy source, and glucose uptake can be stimulated by insulin in dysfunctional myocardium.[4] Currently, the degree of myocardial insulin sensitivity in patients with whole-body insulin resistance remains under investigation. It has been suggested that myocardial glucose uptake in type 2 diabetic and nondiabetic patients with and without coronary artery disease (CAD) is similar to that of healthy subjects.[5,6] In some studies, myocardial glucose uptake has been noted to differ between groups.[7,8,9,10]

Rosiglitazone is a member of the peroxisome proliferator-activated receptor-γ (PPARγ)-agonists, which are widely used as antidiabetic agents. In addition to the effects on glucose metabolism, rosiglitazone has effects on lipid metabolism, inflammatory responses, and cellular proliferation.[11,12,13] In animal studies, rosiglitazone reduces infarct size and improves ischemia/reperfusion-induced myocardial contractile dysfunction.[14] Furthermore, rosiglitazone treatment restores myocardial glucose uptake during ischemia and thus protects myocardium from ischemic injury.[15] In humans, rosiglitazone reduces whole-body insulin resistance by its insulin-sensitizing effect on muscle, adipose tissue, and liver.[16,17,18] Previously, we have shown that rosiglitazone improves myocardial glucose uptake in patients with uncomplicated type 2 diabetes.[19] To our knowledge, the effect of rosiglitazone on myocardial metabolism in patients with type 2 diabetes and CAD has not been previously evaluated.

The purpose of this study was to determine whether rosiglitazone therapy improves myocardial glucose uptake in the regions of abnormal myocardial perfusion in patients with type 2 diabetes and CAD. Exercise-rest single-photon emission tomography (SPECT) perfusion imaging and coronary angiography were performed to locate the region with exercise-induced ischemia and coronary artery stenosis. Myocardial glucose uptake was measured during euglycemic-hyperinsulinemic clamp with positron emission tomography (PET) and [18F]fluoro-2-deoxy-D-glucose (FDG) at baseline and after a 16-week rosiglitazone or placebo intervention period.


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