Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation
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 obstruc...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
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Wiley
2016
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| Online Access: | https://eprints.nottingham.ac.uk/35466/ |
| _version_ | 1848795084618727424 |
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| author | 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. |
| author_facet | 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. |
| author_sort | Mansor, Latt S. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:26:28Z |
| format | Article |
| id | nottingham-35466 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:26:28Z |
| publishDate | 2016 |
| publisher | Wiley |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-354662020-05-04T17:31:55Z https://eprints.nottingham.ac.uk/35466/ 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. 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. Wiley 2016-01-15 Article PeerReviewed 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. 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 http://onlinelibrary.wiley.com/doi/10.1113/JP271242/abstract doi:10.1113/JP271242 doi:10.1113/JP271242 |
| spellingShingle | 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. Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation |
| title | Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation |
| title_full | Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation |
| title_fullStr | Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation |
| title_full_unstemmed | Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation |
| title_short | Increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation |
| title_sort | increased oxidative metabolism following hypoxia in the type 2 diabetic heart, despite normal hypoxia signalling and metabolic adaptation |
| url | https://eprints.nottingham.ac.uk/35466/ https://eprints.nottingham.ac.uk/35466/ https://eprints.nottingham.ac.uk/35466/ |