Chen Tong, Liu Yan-Lan, Qiu Hui-Na, Lin Chen-Ying, Wu Fan, Li Jing-Bo, Lin Jing-Na
School of Medicine, Nankai University, Tianjin, China.
Department of Endocrinology, Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin, 300121, China.
Diabetol Metab Syndr. 2025 Jun 23;17(1):239. doi: 10.1186/s13098-025-01825-2.
Metformin is a widely used antidiabetic agent for obesity-related type 2 diabetes mellitus, providing significant health benefits such as reduced blood glucose levels and body weight. Emerging evidence suggests that metformin may play a beneficial role in delaying aging. However, the causal relationship between metformin use and frailty index (FI) remains uncertain and warrants further investigation. This study aimed to explore the genetically predicted causal relationship between metformin targets and FI.
A two-sample Mendelian randomization (MR) analysis was conducted. Genetic proxies for the target effects of metformin were identified as single nucleotide polymorphisms (SNPs) associated with body weight and corresponding gene expression levels. Summary statistics for the FI were obtained from the genome-wide association study (GWAS) meta-analysis. Additionally, a two-step MR approach was employed to explore whether glycated haemoglobin (HbA1c) exhibits a mediating effect on the relationship between body weight and frailty risk. In the MR analysis, the inverse variance weighted method served as the primary analytical approach, supplemented by sensitivity analyses.
A total of 10 SNPs were included as genetic predictors of metformin. The average effect of the genetic proxies for metformin targets, equivalent to a 1 standard deviation reduction in body weight, was associated with a reduced FI (β: -0.41, 95% CI: -0.74 to -0.07, P = 0.017). Notably, weight reduction induced by the target Mitochondrial complex I (MCI) showed a role in reducing FI. Furthermore, HbA1c mediated 5.5% of the total effect of body weight on FI.
The findings of this study support the notion that metformin may reduce frailty risk through the target MCI, with this effect potentially being partially attributable to weight reduction. These findings provide new insights for developing therapeutic strategies targeting aging and frailty prevention.
二甲双胍是一种广泛用于治疗肥胖相关2型糖尿病的抗糖尿病药物，具有显著的健康益处，如降低血糖水平和体重。新出现的证据表明，二甲双胍可能在延缓衰老方面发挥有益作用。然而，二甲双胍使用与衰弱指数（FI）之间的因果关系仍不确定，值得进一步研究。本研究旨在探讨二甲双胍靶点与FI之间的遗传预测因果关系。
进行了两样本孟德尔随机化（MR）分析。二甲双胍靶点效应的遗传代理被确定为与体重和相应基因表达水平相关的单核苷酸多态性（SNP）。FI的汇总统计数据来自全基因组关联研究（GWAS）荟萃分析。此外，采用两步MR方法探讨糖化血红蛋白（HbA1c）是否对体重与衰弱风险之间的关系具有中介作用。在MR分析中，逆方差加权法作为主要分析方法，并辅以敏感性分析。
共有10个SNP被纳入作为二甲双胍的遗传预测指标。二甲双胍靶点遗传代理的平均效应，相当于体重降低1个标准差，与FI降低相关（β：-0.41，95%CI：-0.74至-0.07，P = 0.017）。值得注意的是，由靶点线粒体复合物I（MCI）诱导的体重减轻在降低FI方面发挥了作用。此外，HbA1c介导了体重对FI总效应的5.5%。
本研究结果支持二甲双胍可能通过靶点MCI降低衰弱风险的观点，这种效应可能部分归因于体重减轻。这些发现为制定针对衰老和衰弱预防的治疗策略提供了新的见解。
