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-17-36 and GLP-19-36 , 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-17-36 and GLP-19-36 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-17-36 and GLP-19-36 , respectively. Differentially expressed gene analysis reveals that possible targets of GLP-17-36 involve the regulation of mitotic nuclear division and
extracellular matrix-receptor interaction, while possible targets of GLP-19-36 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.