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

Abstract

Key pointsr Adaptation to hypoxia makes the heart more oxygen efficient, by metabolising more glucose.In contrast, type 2 diabetes makes the heart metabolise more fatty acids.r Diabetes increases the chances of the heart being exposed to hypoxia, but whether the diabetic heart can adapt and respond is unknown.r In this study we show that diabetic hearts retain the ability to adapt their metabolism in response to hypoxia, with functional hypoxia signalling pathways.r However, the hypoxia-induced changes in metabolism are additive to abnormal baseline metabolism, resulting in hypoxic diabetic hearts metabolising more fat and less glucose than controls. This stops the diabetic heart being able to recover its function when stressed.r These results demonstrate that the diabetic heart retains metabolic flexibility to adapt to hypoxia, but is hindered by the baseline effects of the disease. This increases our understanding of how the diabetic heart is affected by hypoxia-associated complications of the disease.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.

Assessing the effect of hypoxia on cardiac metabolism using hyperpolarized 13C magnetic resonance spectroscopy

“…Our 3 week hypoxic exposure resulted in no metabolic differences in the conversion of HP pyruvate to lactate or bicarbonate in comparison with normoxic data, as supported by measures of PDK and LDH expression. Previous studies from our group have shown that this 3 week protocol of chronic hypoxia at 11% oxygen is sufficient to metabolically reprogram the heart specifically to become more oxygen‐efficient . Further, studies in animal models of hypertrophy have revealed unchanged PDH activity and no differences in PDK isoforms, which appeared at odds with cellular studies on hypoxia.…”

“…Previous studies from our group have shown that this 3 week protocol of chronic hypoxia at 11% oxygen is sufficient to metabolically reprogram the heart specifically to become more oxygen-efficient. 5 Further, studies in animal models of hypertrophy have revealed unchanged PDH activity 47,48 and no differences in PDK isoforms, which appeared at odds with cellular studies on hypoxia. Our data on healthy animals exposed to 3 weeks of hypoxia contribute to these observations and may in future help explain the situation in disease.…”

“…1,2 Prolonged and severe hypoxia requires reprogramming of cardiac metabolism; the heart downregulates oxygen-consuming processes and upregulates glycolysis in an attempt to maximize ATP production under oxygen-restricted conditions. [3][4][5] The effects of chronic hypoxia are observed in response to high altitude, 6 or as a factor in many pathological conditions; examples include chronic obstructive pulmonary disease, 7 complications in pregnancy, 8 sleep apnoea, 9 myocardial infarction (the peri-infarct region) 10 and heart failure. 11 However, much of this existing literature relies on ex vivo assessment of the metabolic changes that occur.…”

Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia improves acute hypoxic tolerance

“…; Mansor et al . ). More detailed information on cardiac responses to hypoxia is therefore needed in order to potentially offer therapies for cardiac disease by identifying intermediate metabolic targets.…”

“…; Mansor et al . ), which involves a period of acclimation similar to that employed by humans in transition to high altitude (Holloway et al . ).…”