Insulin resistance improves metabolic and contractile efficiency in stressed rat heart

FASEB J. 2012 Aug;26(8):3118-26. doi: 10.1096/fj.12-208991. Epub 2012 May 18.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dietary Sucrose / administration & dosage
  • Dietary Sucrose / pharmacology
  • Down-Regulation
  • Glucose / metabolism
  • Heart / physiology*
  • In Vitro Techniques
  • Insulin / physiology
  • Insulin Resistance / physiology*
  • Ion Channels / metabolism
  • Mitochondrial Proteins / metabolism
  • Myocardial Contraction / drug effects
  • Myocardium / metabolism*
  • Oleic Acid / metabolism
  • Perfusion
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Stress, Physiological / physiology*
  • Uncoupling Protein 3

Substances

  • Dietary Sucrose
  • Insulin
  • Ion Channels
  • Mitochondrial Proteins
  • Ucp3 protein, rat
  • Uncoupling Protein 3
  • Oleic Acid
  • Glucose