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Diabetes is a global epidemic, with cardiovascular disease being the leading cause of death in diabetic patients. There is a pressing need for an in vitro model to aid understanding of the mechanisms driving diabetic heart disease, and to provide an accurate, reliable tool for drug testing. Human induced-pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have potential as a disease modelling tool. There are several factors that drive molecular changes inside cardiomyocytes contributing to diabetic cardiomyopathy, including hyperglycaemia, lipotoxicity and hyperinsulinemia. Here we discuss these factors and how they can be seen in animal models and utilised in cell culture to mimic the diabetic heart. The use of human iPSC-CMs will allow for a greater understanding of disease pathogenesis and open up new avenues for drug testing. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) impairs hypoxia-inducible factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischemic remodeling observed following myocardial infarction in T2D. Molidustat is an HIF stabilizer currently undergoing clinical trials for the treatment of renal anemia associated with chronic kidney disease; however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. In human cardiomyocytes, molidustat stabilized HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signaling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, while suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment. In conclusion, pharmacological HIF1α stabilization can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart. [ABSTRACT FROM AUTHOR]