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

Area of Science:

• Cellular and Molecular Biology
• Endocrinology and Metabolism
• Gerontology

Background:

• Telomere length is a biomarker for aging, and diabetes is linked to shorter telomeres.
• Metformin is a common anti-diabetic drug with potential effects on cellular aging processes.

Purpose of the Study:

• To investigate the association between metformin use and telomere attrition rate in type 2 diabetes patients.
• To elucidate the underlying molecular mechanisms of metformin's effect on telomere length.

Main Methods:

• Leukocyte telomere length measured using the telomere restriction fragment assay in 111 healthy individuals and 73 type 2 diabetes patients on metformin.
• mRNA and protein expression studies of telomere length regulators.
• In vitro studies using BJ fibroblast cell line treated with metformin, including gene expression and chromatin immunoprecipitation (ChIP).

Main Results:

• Metformin significantly reduced telomere attrition in diabetic patients compared to healthy individuals.
• Diabetic females showed increased telomere length, while males exhibited reduced attrition rates.
• Metformin dose-dependently slowed telomere attrition in fibroblasts, increasing RAP1 protein via PGC-1α-dependent FOXO3a recruitment to the RAP1 promoter.

Conclusions:

• Metformin is associated with decreased telomere attrition and increased telomeric protein RAP1 expression in type 2 diabetes patients and a fibroblast model.
• A novel PGC-1α-FOXO3a-RAP1 signaling axis links metformin to telomere protection, with a notable effect in females.