Myocardial insulin resistance, metabolic stress and autophagy in diabetes

Kimberley M. Mellor, James R. Bell, Rebecca H. Ritchie, Lea Md Delbridge

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17 Citations (Scopus)

Abstract

Clinical studies in humans strongly support a link between insulin resistance and non-ischaemic heart failure. The occurrence of a specific insulin-resistant cardiomyopathy, independent of vascular abnormalities, is now recognized. The progression of cardiac pathology linked with insulin resistance is poorly understood. Cardiac insulin resistance is characterized by reduced availability of sarcolemmal Glut-4 transporters and consequent lower glucose uptake. A shift away from glycolysis towards fatty acid oxidation for ATP supply is apparent and is associated with myocardial oxidative stress. Reliance of cardiomyocyte excitation-contraction coupling on glycolytically derived ATP supply potentially renders cardiac function vulnerable to the metabolic remodelling adaptations observed in diabetes development. Findings from Glut-4-knockout mice demonstrate that cardiomyocytes with extreme glucose uptake deficiency exhibit cardiac hypertrophy and marked excitation-contraction coupling abnormalities characterized by reduced sarcolemmal Ca2+ influx and sarcoplasmic reticulum Ca2+ uptake. The 'milder' phenotype fructose-fed mouse model of type 2 diabetes does not show evidence of cardiac hypertrophy, but cardiomyocyte loss linked with autophagic activation is evident. Fructose feeding induces a marked reduction in intracellular Ca2+ availability with myofilament adaptation to preserve contractile function in this setting. The cardiac metabolic adaptations of two load-independent models of diabetes, namely the Glut-4-deficient mouse and the fructose-fed mouse are contrasted. The role of autophagy in diabetic cardiopathology is evaluated and anomalies of type 1 versus type 2 diabetic autophagic responses are highlighted.

Original languageEnglish
Pages (from-to)56-61
Number of pages6
JournalClinical and Experimental Pharmacology and Physiology
Volume40
Issue number1
DOIs
Publication statusPublished - 1 Jan 2013
Externally publishedYes

Keywords

  • Autophagy
  • Cardiac
  • Diabetes
  • Excitation-contraction coupling
  • Insulin resistance
  • Metabolism

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