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Myocardial insulin resistance, metabolic stress and autophagy in diabetes
Author(s) -
Mellor Kimberley M,
Bell James R,
Ritchie Rebecca H,
Delbridge Lea MD
Publication year - 2013
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2012.05738.x
Subject(s) - insulin resistance , medicine , endocrinology , diabetes mellitus , glycolysis , diabetic cardiomyopathy , insulin , cardiomyopathy , heart failure , oxidative stress , type 2 diabetes , cardiac function curve , biology , metabolism
Summary 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 G lut‐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 G lut‐4‐knockout mice demonstrate that cardiomyocytes with extreme glucose uptake deficiency exhibit cardiac hypertrophy and marked excitation–contraction coupling abnormalities characterized by reduced sarcolemmal Ca 2+ influx and sarcoplasmic reticulum Ca 2+ 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 Ca 2+ availability with myofilament adaptation to preserve contractile function in this setting. The cardiac metabolic adaptations of two load‐independent models of diabetes, namely the G lut‐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.