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

Mansor, Latt S.; Mehta, Keshavi; Aksentijevic, Dunja; Carr, Carolyn A.; Lund, Trine; Cole, Mark A.; Page, Lydia Le; Sousa Fialho, Maria da Luz; Shattock, Michael J.; Aasum, Ellen; Clarke, Kieran; Tyler, Damian J.; Heather, Lisa C.

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.

Citation

Mansor, L. S., Mehta, K., Aksentijevic, D., Carr, C. A., Lund, T., Cole, M. A., …Heather, L. 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), 307-320. https://doi.org/10.1113/JP271242

• Journal Article Type: Article
• Acceptance Date: Nov 10, 2015
• Online Publication Date: Dec 20, 2015
• Publication Date: Jan 15, 2016
• Deposit Date: Jul 27, 2016
• Publicly Available Date: Jul 27, 2016
• Journal: Journal of Physiology
• Print ISSN: 0022-3751
• Electronic ISSN: 1469-7793
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 594
• Issue: 2
• Pages: 307-320
• DOI: https://doi.org/10.1113/JP271242
• Public URL: https://nottingham-repository.worktribe.com/output/772585
• Publisher URL: http://onlinelibrary.wiley.com/doi/10.1113/JP271242/abstract
• 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.