Metformin-mediated protection against Immunosenescence in diabetic cardiomyopathy: The potential roles of GDF-15 and klotho proteins

Diabetic cardiomyopathy (DCM) is a global health concern. However, studies examining the effect of metformin on diabetes-induced cardiac myocyte aging are lacking. This study aimed to investigate the protective effect of metformin against DCM involving modulation of macrophage phenotypes, growth differentiation factor-15 (GDF-15), and the anti-aging protein Klotho. Diabetes was induced in male Wistar rats using streptozotocin. Diabetic and nondiabetic rats were treated with metformin (200 mg/kg/day) and saline (control). DCM, inflammation, adhesion molecules, immunometabolic, and GDF-15 biomarkers were assessed using immunoassays. Western blotting was used to analyze Klotho expression. Macrophage phenotypes, senescence-associated-galactosidase (SA-β-gal), and p16^INK4a were examined using immunohistochemistry, whereas the heart sections were histologically examined. The untreated diabetic rats showed increased serum troponin I and creatine kinase-MB levels, reflecting cardiac damage, which was confirmed via morphological changes and senescence. Klotho expression was decreased, indicating cardiac aging. Treatment with metformin reduced the heart weight-body weight ratio and lowered cardiac injury, inflammation, and adhesion molecule biomarker levels. It also reversed the histopathological changes induced by diabetes. It shifted macrophage polarization toward the M2 phenotype, decreased p16^INK4a and SA-β-gal expression, and enhanced Klotho and GDF-15 expression. These findings revealed that diabetes induces cardiac aging by increasing senescence markers and decreasing the expression of Klotho. Metformin treatment protects against DCM by modulating macrophage phenotypes, attenuating immunosenescence-related dysregulation, and enhancing GDF-15 and Klotho expressions. Thus, metformin has potential clinical implications in alleviating DCM.