title: Single-dose dexamethasone induces whole-body insulin resistance and alters both cardiac fatty acid and carbohydrate metabolism.
abstract: 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.
authors.affiliation: Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, The University of British Columbia, 2146 East Mall, Vancouver, BC, Canada.
authors.forename: Dake
authors.initials: D
authors.lastname: Qi
authors.forename: Thomas
authors.initials: T
authors.lastname: Pulinilkunnil
authors.forename: Ding
authors.initials: D
authors.lastname: An
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Ghosh
authors.forename: Ashraf
authors.initials: A
authors.lastname: Abrahani
authors.forename: John Andrew
authors.initials: JA
authors.lastname: Pospisilik
authors.forename: Roger
authors.initials: R
authors.lastname: Brownsey
authors.forename: Rich
authors.initials: R
authors.lastname: Wambolt
authors.forename: Michael
authors.initials: M
authors.lastname: Allard
authors.forename: Brian
authors.initials: B
authors.lastname: Rodrigues
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism; D003331:Coronary Vessels / Q000201:enzymology; D003907:Dexamethasone / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005227:Fatty Acids / Q000378:metabolism*; D005938:Glucocorticoids / Q000008:administration & dosage*; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance; D007527:Isoenzymes / Q000378:metabolism; D008071:Lipoprotein Lipase / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017208:Rats, Wistar; D013311:Streptozocin / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
chemical_list: D005227:Fatty Acids; D005938:Glucocorticoids; D007328:Insulin; D007527:Isoenzymes; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014280:Triglycerides; D013311:Streptozocin; D003907:Dexamethasone; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D017346:Protein Serine-Threonine Kinases; D008071:Lipoprotein Lipase; D005947:Glucose