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(Circulation. 2005;111:2291-2298.)
© 2005 American Heart Association, Inc.

Coronary Heart Disease

Coronary Circulatory Dysfunction in Insulin Resistance, Impaired Glucose Tolerance, and Type 2 Diabetes Mellitus

John O. Prior, MD, PhD; Manuel J. Quiñones, MD; Miguel Hernandez-Pampaloni, MD, PhD; Alvaro D. Facta, MD; Thomas H. Schindler, MD; James W. Sayre, PhD; Willa A. Hsueh, MD; Heinrich R. Schelbert, MD, PhD

From the Departments of Molecular and Medical Pharmacology and Medicine (J.O.P., M.H.-P., A.D.F., T.H.S., J.W.S., H.R.S.), Division of Endocrinology, Diabetes and Hypertension (M.J.Q., W.A.H.), David Geffen School of Medicine at UCLA, Los Angeles, Calif.

Correspondence to Heinrich R. Schelbert, MD, PhD, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Box 956948, B2-085J CHS, 10833 Le Conte Ave, Los Angeles, CA 90095-6948. E-mail HSchelbert{at}mednet.ucla.edu

Received September 14, 2004; revision received January 7, 2005; accepted January 20, 2005.

Background— Abnormal coronary endothelial reactivity has been demonstrated in diabetes and is associated with an increased rate of cardiovascular events. Our objectives were to investigate the presence of functional coronary circulatory abnormalities over the full spectrum of insulin resistance and to determine whether these would differ in severity with more advanced states of insulin resistance.

Methods and Results— Myocardial blood flow (MBF) was measured with positron emission tomography and ¹³N-ammonia to characterize coronary circulatory function in states of insulin resistance without carbohydrate intolerance (IR), impaired glucose tolerance (IGT), and normotensive and hypertensive type 2 diabetes mellitus (DM) compared with insulin-sensitive (IS) individuals. Indices of coronary function were total vasodilator capacity (mostly vascular smooth muscle–mediated) during pharmacological vasodilation and the nitric oxide–mediated, endothelium-dependent vasomotion in response to cold pressor testing. Total vasodilator capacity was similar in normoglycemic individuals (IS, IR, and IGT), whereas it was significantly decreased in normotensive (–17%) and hypertensive (–34%) DM patients. Compared with IS, endothelium-dependent coronary vasomotion was significantly diminished in IR (–56%), as well as in IGT and normotensive and hypertensive diabetic patients (–85%, –91%, and –120%, respectively).

Conclusions— Progressively worsening functional coronary circulatory abnormalities of nitric oxide–mediated, endothelium-dependent vasomotion occur with increasing severity of insulin-resistance and carbohydrate intolerance. Attenuated total vasodilator capacity accompanies the more clinically evident metabolic abnormalities in diabetes.

Key Words: blood flow • diabetes mellitus • endothelium • hypertension

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