Inhibition of GCN2 Alleviates Cardiomyopathy in Type 2 Diabetic Mice via Attenuating Lipotoxicity and Oxidative Stress

Diabetic cardiomyopathy (DCM) is a heart condition that affects individuals with diabetes and is a leading cause of mortality. Our previous research indicated that the deletion of the general control nonderepressible 2 (GCN2) kinase improves cardiac function in diabetic mice. This study aimed to investigate the protective effects of GCN2iB, a GCN2 inhibitor, in type 2 diabetic (T2D) mice induced by a high-fat diet (HFD) combined with low-dose streptozotocin (STZ) treatment or by deletion of the leptin receptor (db/db).

Treatment with GCN2iB (3 mg/kg every other day) for six weeks resulted in significant reductions in fasting blood glucose levels and body weight, as well as improvements in left ventricular ejection fraction. Additionally, GCN2iB treatment reduced myocardial fibrosis, lipid accumulation, and oxidative stress in the hearts of T2D mice. These effects were associated with decreased expression of lipid metabolism-related genes and increased expression of antioxidative genes.

Untargeted metabolomics and RNA sequencing analyses revealed that GCN2iB had a significant impact on myocardial metabolomic and gene expression profiles. Notably, GCN2iB increased levels of myocardial phosphocreatine and taurine while upregulating genes involved in oxidative phosphorylation.

In summary, our data demonstrate that GCN2iB effectively protects against cardiac dysfunction in T2D mice, suggesting it could serve as a promising new drug candidate for the treatment of DCM.