AimsThe type 2 diabetic heart oxidizes more fat and less glucose, which can impair metabolic flexibility and function. Increased sarcolemmal fatty acid translocase (FAT/CD36) imports more fatty acid into the diabetic myocardium, feeding increased fatty acid oxidation and elevated lipid deposition. Unlike other metabolic modulators that target mitochondrial fatty acid oxidation, we proposed that pharmacologically inhibiting fatty acid uptake, as the primary step in the pathway, would provide an alternative mechanism to rebalance metabolism and prevent lipid accumulation following hypoxic stress.Methods and resultsHearts from type 2 diabetic and control male Wistar rats were perfused in normoxia, hypoxia and reoxygenation, with the FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) infused 4 min before hypoxia. SSO infusion into diabetic hearts decreased the fatty acid oxidation rate by 29% and myocardial triglyceride concentration by 48% compared with untreated diabetic hearts, restoring fatty acid metabolism to control levels following hypoxia-reoxygenation. SSO infusion increased the glycolytic rate by 46% in diabetic hearts during hypoxia, increased pyruvate dehydrogenase activity by 53% and decreased lactate efflux rate by 56% compared with untreated diabetic hearts during reoxygenation. In addition, SSO treatment of diabetic hearts increased intermediates within the second span of the Krebs cycle, namely fumarate, oxaloacetate, and the FAD total pool. The cardiac dysfunction in diabetic hearts following decreased oxygen availability was prevented by SSO-infusion prior to the hypoxic stress. Infusing SSO into diabetic hearts increased rate pressure product by 60% during hypoxia and by 32% following reoxygenation, restoring function to control levels.ConclusionsDiabetic hearts have limited metabolic flexibility and cardiac dysfunction when stressed, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel therapeutic approach not only reduces fat oxidation but also lipotoxicity, by targeting the primary step in the fatty acid metabolism pathway.

AimsThe type 2 diabetic heart is metabolically abnormal, which has been implicated in decreased recovery of diabetic hearts post-ischaemia. We propose that reducing sarcolemmal fatty acid uptake, by inhibiting fatty acid translocase (FAT/CD36), may provide a novel mechanism to rebalance metabolism, and hypothesise this may improve function in the diabetic heart.MethodsType 2 diabetic and control rat hearts were perfused under normoxia, hypoxia, and reoxygenation, with radioactive substrates for measurement of metabolism in the contracting heart. The FAT/CD36 inhibitor sulfo-N-succinimidyl oleate (SSO) was infused 5 min prior to hypoxia.ResultsIn normoxia, diabetic hearts had increased fatty acid oxidation rates (39%) and decreased glycolysis (59%) compared with controls. During hypoxia, fatty acid oxidation was suppressed to low levels in all hearts, however, diabetic hearts did not concomitantly upregulate anaerobic glycolysis to the same extent as controls. During reperfusion, metabolism returned to normoxic rates, but was accompanied by a 55% increase in myocardial lipids in diabetic hearts. Infusing SSO prior to hypoxia increased glycolysis in diabetic hearts. SSO reduced fatty acid oxidation rates in diabetic hearts to control levels at reoxygenation, accompanied by prevention of excess myocardial lipid deposition. These metabolic changes resulted in a 27% improvement in contractile recovery in diabetic hearts treated with SSO.ConclusionsDiabetic hearts have limited metabolic flexibility when challenged with hypoxia, which can be rapidly rectified by reducing fatty acid uptake with the FAT/CD36 inhibitor, SSO. This novel approach provides a mechanism to prevent lipotoxicity and improve contractile function in the diabetic heart.