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Diabetes 53:1790-1797, 2004
© 2004 by the American Diabetes Association, Inc.

Single-Dose Dexamethasone Induces Whole-Body Insulin Resistance and Alters Both Cardiac Fatty Acid and Carbohydrate Metabolism

Dake Qi1, Thomas Pulinilkunnil1, Ding An1, Sanjoy Ghosh1, Ashraf Abrahani1, John Andrew Pospisilik2, Roger Brownsey3, Rich Wambolt4, Michael Allard4, and Brian Rodrigues1

1 Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada
2 Department of Physiology, University of British Columbia, Vancouver, British Columbia, Canada
3 Department of Biochemistry, University of British Columbia, Vancouver, British Columbia, Canada
4 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

Glucocorticoids impair insulin sensitivity. Because insulin resistance is closely linked to increased incidence of cardiovascular diseases and given that metabolic abnormalities have been linked to initiation of heart failure, we examined the acute effects of dexamethasone (DEX) on rat cardiac metabolism. Although injection of DEX for 4 h was not associated with hyperinsulinemia, the euglycemic-hyperinsulinemic clamp showed a decrease in glucose infusion rate. Rates of cardiac glycolysis were unaffected, whereas the rate of glucose oxidation following DEX was significantly decreased and could be associated with augmented expression of PDK4 mRNA and protein. Myocardial glycogen content in DEX hearts increased compared with control. Similar to hypoinsulinemia induced by streptozotocin (STZ), hearts from insulin-resistant DEX animals also demonstrated enlargement of the coronary lipoprotein lipase (LPL) pool. However, unlike STZ, DEX hearts showed greater basal release of LPL and were able to maintain their high heparin-releasable LPL in vitro. This effect could be explained by the enhanced LPL mRNA expression following DEX. Our data provide evidence that in a setting of insulin resistance, an increase in LPL could facilitate increased delivery of fatty acid to the heart, leading to excessive triglyceride storage. It has not been determined whether these acute effects of DEX on cardiac metabolism can be translated into increased cardiovascular risk.

Address correspondence and reprint requests to Dr. B. Rodrigues, Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada. E-mail: rodrigue{at}unixg.ubc.ca

Abbreviations: DCA, dichloroacetate; DEX, dexamethasone; HSPG, heparan sulfate proteoglycan; LPL, lipoprotein lipase; PDC, pyruvate dehydrogenase complex; PDK, pyruvate dehydrogenase kinase; STZ, streptozotocin


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