Glucagon-Like Peptide-1 (GLP-1) Rescue Diabetic Cardiac Dysfuntions in Human iPSC-Derived Cardiomyocytes

Glucagon-like peptide-1 (GLP-1) can improve cardiac function and cardiovascular outcomes in diabetic cardiomyopathy; however, the beneficial effect of GLP-1 on human diabetic cardiomyocytes (DCMs) and its mechanism have not been fully elucidated. Here, the DCMs model by human-induced pluripotent stem cells-derived cardiomyocytes is developed. Two subtypes of GLP-1, GLP-1_7-36 and GLP-1_9-36 , are evaluated for their efficacy on the DCMs model. Diabetogenic condition is sufficient to induce most characteristics of diabetic cardiomyopathy in vitro, such as cardiac hypertrophy, lipid accumulation, impaired calcium transients, and abnormal electrophysiological properties. GLP-1_7-36 and GLP-1_9-36 can restore cardiomyocyte hypertrophic phenotype, impaired calcium transient frequency, abnormal action potential amplitude, depolarization, and repolarization velocity. Interestingly, RNA-seq reveals different pathways altered by GLP-1_7-36 and GLP-1_9-36 , respectively. Differentially expressed gene analysis reveals that possible targets of GLP-1_7-36 involve the regulation of mitotic nuclear division and extracellular matrix-receptor interaction, while possible targets of GLP-1_9-36 involve kinetochore assembly, and the complement and coagulation cascades. This study demonstrates the therapeutic effects of GLP-1 on human DCMs and provides a novel platform to unveil the cellular mechanisms of diabetic cardiomyopathy, shedding light on discovering better targets for novel therapeutic interventions.