Myocardial insulin resistance, metabolic stress and autophagy in diabetes.

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 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 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.

• Authors: Kimberley M Mellor, James R Bell, Rebecca H Ritchie, Lea M D Delbridge
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 40 Issue 1 Pg. 56-61 (Jan 2013) ISSN: 1440-1681 [Electronic] Australia
• PMID: 22804725 (Publication Type: Journal Article)
• Copyright: © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Wiley Publishing Asia Pty Ltd.

Chemical References

• Glucose Transporter Type 4
• Slc2a4 protein, mouse
• Fructose
• Glucose
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cardiomegaly (metabolism, physiopathology)
• Diabetes Mellitus, Type 1 (metabolism, physiopathology)
• Diabetes Mellitus, Type 2 (metabolism, pathology)
• Fructose (metabolism)
• Glucose (metabolism)
• Glucose Transporter Type 4 (metabolism)
• Heart (physiopathology)
• Insulin Resistance (physiology)
• Mice
• Mice, Inbred C57BL
• Myocardium (metabolism, pathology)
• Myocytes, Cardiac (metabolism, pathology)
• Myofibrils (metabolism, pathology)
• Sarcoplasmic Reticulum (metabolism, pathology)
• Stress, Physiological (physiology)