Metformin exhibits gender specific impact on telomere dynamics by enhancing RAP1 expression in type-2 diabetes mellitus.

Telomere length serves as a critical biomarker of ageing, and diabetes is associated with shorter telomeres. This study aims to investigate the association and underlying molecular mechanism between telomere attrition rate in healthy individuals and patients with type 2 diabetes who consume the anti-diabetic drug metformin. Leukocyte telomere length was measured using the telomere restriction fragment assay in 111 healthy individuals and in 73 individuals with type 2 diabetes who were consuming metformin. Telomere length-regulating mRNA and protein expression studies were performed. The BJ fibroblast cell line was treated with different concentrations of metformin, and telomere length analysis, gene expression and chromatin immunoprecipitation (ChIP) were performed. Compared to healthy volunteers, telomere attrition was markedly reduced in diabetic patients who were on metformin. Diabetic females, in particular, showed an increase in telomere length, while males showed a reduction in the telomere attrition rate. In the BJ fibroblasts, metformin slowed telomere attrition in a dose-dependent manner. Molecular studies revealed that metformin treatment resulted in increased expression of telomeric protein RAP1 via enhanced PGC1α-dependent Foxo3a recruitment to the RAP1 promoter. Metformin is associated with decreased telomere attrition and increased telomeric protein RAP1 expression in both diabetic patients and in the fibroblast model. The effect is particularly significant in females. To our knowledge, this is the first study to identify a PGC-1α-FOXO3a-RAP1 signaling axis linking metformin exposure to telomere protection in human diabetic cohorts and to mechanistically validate this pathway using a fibroblast model.