Published Online
on April 25, 2005

A more recent version of this article appeared on May 10, 2005

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Submitted on September 14, 2004
Revised on January 7, 2005
Accepted on January 20, 2005

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, and 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.

^* To whom correspondence should be addressed. E-mail: HSchelbert{at}mednet.ucla.edu.

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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