title: Insulin resistance improves metabolic and contractile efficiency in stressed rat heart.
abstract: Insulin resistance is a prominent feature in heart failure, while hyperglycemia impairs cardiac contraction. We propose that decreased insulin-mediated glucose uptake by the heart preserves cardiac function in response to metabolic and hemodynamic stress. To test this hypothesis, we fed rats a high-sucrose diet (HSD). Energy substrate metabolism and cardiac work were determined ex vivo in a sequential protocol simulating metabolic and hemodynamic stress. Compared to chow-fed, control rats, HSD impaired myocardial insulin responsiveness and induced profound metabolic changes in the heart, characterized by reduced rates of glucose uptake (7.91 ± 0.30 vs. 10.73 ± 0.67 μmol/min/g dry weight; P<0.001) but increased rates of glucose oxidation (2.38 ± 0.17 vs. 1.50 ± 0.15 μmol/min/g dry weight; P<0.001) and oleate oxidation (2.29 ± 0.11 vs. 1.96 ± 0.12 μmol/min/g dry weight; P<0.05). Tight coupling of glucose uptake and oxidation and improved cardiac efficiency were associated with a reduction in glucose 6-phosphate and oleoyl-CoA levels, as well as a reduction in the content of uncoupling protein 3. Our results suggest that insulin resistance lessens fuel toxicity in the stressed heart. This calls for a new exploration of the mechanisms regulating substrate uptake and oxidation in the insulin-resistant heart.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, University of Texas Medical School at Houston, Houston, Texas 77030, USA. heinrich.taegtmeyer@uth.tmc.edu
authors.forename: Romain
authors.initials: R
authors.lastname: Harmancey
authors.forename: Truong N
authors.initials: TN
authors.lastname: Lam
authors.forename: Genna M
authors.initials: GM
authors.lastname: Lubrano
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Guthrie
authors.forename: Deborah
authors.initials: D
authors.lastname: Vela
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
mesh_terms: D000818:Animals; D019422:Dietary Sucrose / Q000008:administration & dosage / Q000494:pharmacology; D015536:Down-Regulation; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D007473:Ion Channels / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000502:physiology*; D000071247:Uncoupling Protein 3
chemical_list: D019422:Dietary Sucrose; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604394:Ucp3 protein, rat; D000071247:Uncoupling Protein 3; D019301:Oleic Acid; D005947:Glucose