Diabetic cardiomyopathy – an epidemic disease
Globally, diabetes is an epidemic disease with a specific cardiopathology independent of vascular and other cardiovascular risk profile. In the diabetic heart, one of the first signs of pathology is deterioration in the capacity of the heart to relax (in diastole) – and later signs of active pump failure (in systole) emerge. Our work focuses on understanding the mechanisms of both diastolic and systolic dysfunction, examining how circulating and locally produced hormones impact on cardiopathology and identifying potential molecular targets for intervention. Using genetic and experimental models of type 1 and type 2 diabetes we are investigating the structural bases for relaxation abnormality in the diabetic heart – evaluating active and passive components of stiffness which reflect both cardiac muscle cell and extracellular matrix pathology. We were the first to show that in a type 2 setting of insulin resistance there is heightened cardiac myocyte autophagic activity – a process by which intracellular energy and structural components are broken down through 'bulk' enzyme degradation processes. In excess, autophagy is associated with induction of cell death – and our evidence shows this cell loss is linked with increased interstitial fibrosis in the cardiac tissue. Most recently we have demonstrated that a particular form of autophagy involving glycogen breakdown ( 'glycophagy' ) is prominent in the diabetic heart. With ongoing projects, in close collaboration with the Mellor Laboratory at U Auckland, we are pursuing these lines of evidence in the Lab.
- *Mellor KM, *Varma U, Stapleton DI, Delbridge LM. Cardiomyocyte glycophagy is regulated by insulin and exposure to high extracellular glucose. Am J Physiol Heart Circ Physiol 2014; 306: H1240-5, . Pubmed Link
- *Reichelt ME, *Mellor KM, Curl CL, Stapleton D, Delbridge LM. Myocardial glycophagy - a specific glycogen handling response to metabolic stress is accentuated in the female heart. J Mol Cell Cardiol 2013; 65: 67-75. Pubmed Link
- Reichelt ME, Mellor KM, Bell JR, Chandramouli C, Headrick JP, Delbridge LM. Sex, sex steroids, and diabetic cardiomyopathy: making the case for experimental focus. Am J Physiol Heart Circ Physiol 2013; 305: H779-92. Pubmed Link
- Mellor KM, Wendt IR, Ritchie RH, Delbridge LM. Fructose diet treatment in mice induces fundamental disturbance of cardiomyocyte Ca2+ handling and myofilament responsiveness. Am J Physiol Heart Circ Physiol 2012; 15: 302: H964-72. Pubmed Link
- Mellor KM; Reichelt ME; Delbridge LMD. Autophagy anomalies in the diabetic myocardium. Autophagy Commentary 2011; 7: 1261-1265. Pubmed Link
- Mellor KM; Bell JR; Young MJ; Ritchie RH; Delbridge LMD. Myocardial autophagy activation and suppressed growth signaling is associated with insulin resistance in fructose-fed mice. Journal of Molecular and Cellular Cardiology 2011; 50: 1035-43. Pubmed Link
Mellor Laboratory at the University of Auckland
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