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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.

Original publication

DOI

10.2337/db21-0398

Type

Journal article

Journal

Diabetes

Publication Date

11/2021

Volume

70

Pages

2518 - 2531

Keywords

Adaptation, Physiological, Anemia, Sickle Cell, Animals, Cell Line, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Diabetic Cardiomyopathies, Energy Metabolism, Gene Expression Regulation, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Insulin Resistance, Myocytes, Cardiac, Oxygen, Pluripotent Stem Cells, Pyrazoles, Rats, Triazoles