Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation

Mansor, Latt S. and Mehta, Keshavi and Aksentijevic, Dunja and Carr, Carolyn A. and Lund, Trine and Cole, Mark A. and Page, Lydia Le and Sousa Fialho, Maria da Luz and Shattock, Michael J. and Aasum, Ellen and Clarke, Kieran and Tyler, Damian J. and Heather, Lisa C. (2016) Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation. Journal of Physiology, 594 (2). pp. 307-320. ISSN 1469-7793

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Abstract

Hypoxia activates the hypoxia-inducible factor (HIF), promoting glycolysis and suppressing mitochondrial respiration. In the type 2 diabetic heart, glycolysis is suppressed whereas fatty acid metabolism is promoted. The diabetic heart experiences chronic hypoxia as a consequence of increased obstructive sleep apnoea and cardiovascular disease. Given the opposing metabolic effects of hypoxia and diabetes, we questioned whether diabetes affects cardiac metabolic adaptation to hypoxia. Control and type 2 diabetic rats were housed for 3 weeks in normoxia or 11% oxygen. Metabolism and function were measured in the isolated perfused heart using radiolabelled substrates. Following chronic hypoxia, both control and diabetic hearts upregulated glycolysis, lactate efflux and glycogen content and decreased fatty acid oxidation rates, with similar activation of HIF signalling pathways. However, hypoxia-induced changes were superimposed on diabetic hearts that were metabolically abnormal in normoxia, resulting in glycolytic rates 30% lower, and fatty acid oxidation 36% higher, in hypoxic diabetic hearts than hypoxic controls. Peroxisome proliferator-activated receptor α target proteins were suppressed by hypoxia, but activated by diabetes. Mitochondrial respiration in diabetic hearts was divergently activated following hypoxia compared with controls. These differences in metabolism were associated with decreased contractile recovery of the hypoxic diabetic heart following an acute hypoxic insult. In conclusion, type 2 diabetic hearts retain metabolic flexibility to adapt to hypoxia, with normal HIF signalling pathways. However, they are more dependent on oxidative metabolism following hypoxia due to abnormal normoxic metabolism, which was associated with a functional deficit in response to stress.

Item Type: Article
Additional Information: This is the peer reviewed version of the following article: Mansor, L. S., Mehta, K., Aksentijevic, D., Carr, C. A., Lund, T., Cole, M. A., Page, L. L., Sousa Fialho, M. d. L., Shattock, M. J., Aasum, E., Clarke, K., Tyler, D. J. and Heather, L. C. (2016), Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation. J Physiol, 594: 307–320, which has been published in final form at http://dx.doi.org/10.1113/JP271242. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: https://doi.org/10.1113/JP271242
Depositing User: Eprints, Support
Date Deposited: 27 Jul 2016 11:17
Last Modified: 26 Sep 2016 14:52
URI: http://eprints.nottingham.ac.uk/id/eprint/35466

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