Almohaimeed Ghada M, Alonazi Asma S, Alshammari Tahani K, Bin Dayel Anfal F, Alghibiwi Hanan K, Alamin Maha A, Almotairi Ahmad R, Aldawsari Nasser A, Alkhelb Dalal A, Alrasheed Nawal M, Sarawi Wedad S, Alrasheed Nouf M
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Pathology, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
Int Immunopharmacol. 2025 Apr 24;153:114530. doi: 10.1016/j.intimp.2025.114530. Epub 2025 Mar 26.
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 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 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.
糖尿病性心肌病（DCM）是一个全球性的健康问题。然而，关于二甲双胍对糖尿病诱导的心肌细胞衰老影响的研究尚缺乏。本研究旨在探讨二甲双胍对DCM的保护作用，其涉及巨噬细胞表型、生长分化因子15（GDF-15）和抗衰老蛋白α-klotho的调节。使用链脲佐菌素诱导雄性Wistar大鼠患糖尿病。糖尿病大鼠和非糖尿病大鼠分别用二甲双胍（200mg/kg/天）和生理盐水（对照）治疗。使用免疫测定法评估DCM、炎症、黏附分子、免疫代谢和GDF-15生物标志物。采用蛋白质免疫印迹法分析α-klotho的表达。使用免疫组织化学检查巨噬细胞表型、衰老相关β-半乳糖苷酶（SA-β-gal）和p16，而对心脏切片进行组织学检查。未经治疗的糖尿病大鼠血清肌钙蛋白I和肌酸激酶-MB水平升高，反映出心脏损伤，这通过形态学变化和衰老得到证实。α-klotho表达降低，表明心脏衰老。二甲双胍治疗降低了心脏重量与体重比，降低了心脏损伤、炎症和黏附分子生物标志物水平。它还逆转了糖尿病诱导的组织病理学变化。它使巨噬细胞极化转向M2表型，降低p16和SA-β-gal表达，并增强α-klotho和GDF-15表达。这些发现表明，糖尿病通过增加衰老标志物和降低α-klotho的表达来诱导心脏衰老。二甲双胍治疗通过调节巨噬细胞表型、减轻免疫衰老相关的失调以及增强GDF-15和α-klotho表达来预防DCM。因此，二甲双胍在缓解DCM方面具有潜在的临床意义。
