Kuo Chien-Yin, Tsou Sing-Hua, Kornelius Edy, Chan Kuei-Chuan, Chang Kai-Wei, Li Jung-Chi, Huang Chien-Ning, Lin Chih-Li
Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd, Taichung City, 402, Taiwan.
Department of Surgery, Chung Shan Medical University Hospital, Taichung, 402, Taiwan.
Cell Mol Life Sci. 2025 Jan 8;82(1):39. doi: 10.1007/s00018-024-05558-9.
Diabetes is a primary contributor to diabetic cardiomyopathy (DbCM), which is marked by metabolic imbalances such as elevated blood glucose and lipid levels, leading to significant structural and functional alterations in the myocardium. Elevated free fatty acids (FFAs) and hyperglycemia play critical roles in DbCM development, with FFAs inducing insulin resistance in cardiomyocytes and promoting lipid accumulation, resulting in oxidative stress and fibrosis. Current research suggests that glucagon-like peptide-1 (GLP-1) receptor agonists may effectively mitigate DbCM, although an effective treatment for this condition remains elusive, and the precise mechanisms of this protective effect are not fully understood.
In this study, we aimed to replicate diabetic glucolipotoxic conditions by treating differentiated H9c2 cells with high glucose and free fatty acids. Additionally, a diabetic cardiomyopathy model was induced in mice through high-fat diets. Both in vitro and in vivo models were used to investigate the protective effects of liraglutide on cardiomyocytes and elucidate its underlying molecular mechanisms.
Our findings indicate that liraglutide significantly reduces lipid droplet (LD) formation and myocardial fibrosis, as evidenced by decreased expression of fibrosis markers, including TGF-β1 and collagen types I and III. Liraglutide also enhanced AMP-activated protein kinase (AMPK) activation, which improved mitochondrial function, increased antioxidant gene expression, enhanced insulin signaling, and reduced oxidative stress.
These results demonstrate the potential therapeutic role of liraglutide in managing diabetes-related cardiac complications, offering a comprehensive approach to improving cardiac outcomes in patients with diabetes.
糖尿病是糖尿病性心肌病（DbCM）的主要促成因素，其特征是代谢失衡，如血糖和血脂水平升高，导致心肌出现显著的结构和功能改变。游离脂肪酸（FFA）升高和高血糖在DbCM的发展中起关键作用，FFA可诱导心肌细胞产生胰岛素抵抗并促进脂质蓄积，从而导致氧化应激和纤维化。目前的研究表明，胰高血糖素样肽-1（GLP-1）受体激动剂可能有效减轻DbCM，尽管针对这种疾病的有效治疗方法仍然难以捉摸，而且这种保护作用的确切机制尚未完全了解。
在本研究中，我们旨在通过用高糖和游离脂肪酸处理分化的H9c2细胞来模拟糖尿病性糖脂毒性状况。此外，通过高脂饮食在小鼠中诱导建立糖尿病性心肌病模型。体外和体内模型均用于研究利拉鲁肽对心肌细胞的保护作用，并阐明其潜在的分子机制。
我们的研究结果表明，利拉鲁肽可显著减少脂滴（LD）形成和心肌纤维化，这可通过纤维化标志物（包括转化生长因子-β1以及I型和III型胶原）表达降低得到证明。利拉鲁肽还增强了AMP激活的蛋白激酶（AMPK）的活性，这改善了线粒体功能，增加了抗氧化基因表达，增强了胰岛素信号传导，并减少了氧化应激。
这些结果证明了利拉鲁肽在管理糖尿病相关心脏并发症方面的潜在治疗作用，为改善糖尿病患者的心脏预后提供了一种全面的方法。
