Metformin and Molecular Aging in Prediabetes

Plain-language summary

The incidence and prevalence of type 2 diabetes mellitus (T2DM) are increasing globally. The global prevalence of diabetes has nearly doubled since 1980, rising from 4.7% to 8.5% in the adult population. Asian Indians have one of the highest incidence rates of pre-diabetes (10.3%) and type 2 diabetes mellitus (T2DM) (8.8%) among all major ethnic groups, and the conversion from pre-diabetes to diabetes occurs more rapidly in this population. Metformin has been shown to effectively prevent the progression of prediabetes to overt diabetes. Furthermore, metformin improves lifespan in animal models through an anti-ageing pathway driven by mTOR. Metformin has also been shown to protect endothelial cells from hyperglycaemic damage by directly stimulating the expression of Sirtuin-1 (SIRT1), a deacetylase involved in metabolism and longevity by modulating SIRT1 downstream targets FoxO1 and p53/p21. It is important to note thatSIRT1, andmammalian target of rapamycin (mTOR) form a network that connects cellular metabolism and longevity programmes. Only one study is available which has explored the relationship of metformin with longevity. Previous study conducted a single-blind randomized placebo-controlled trial in prediabetic subjects in Italy (n, 38) who received metformin 1500mg/day (n, 19) or placebo (n, 19) for 2 months. They demonstrated that metformin use significantly increased insulin sensitivity and metabolic parameters, SIRT1 gene/protein expression, and SIRT1 promoter chromatin accessibility. They also demonstrated that metformin use increased mTOR gene expression with a concurrent decrease in p70S6K phosphorylation and altered the plasma N-glycan profile. These authors concluded that in individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. The investigators recently did a study on 797 prediabetic women from north India (492 of whom were obese). In this study the investigators reported that age, obesity, and subcutaneous adiposity (predominantly truncal) are the main causes of leukocyte telomere shortening. It is yet unknown how metformin impacts aging-related genes and surrogate markers of ageing in the Asian Indian population. This clinical trial aims to evaluate the effects of metformin treatment on surrogate markers of ageing (leukocyte telomere length and telomerase activity), in the setting of pre-diabetes. We intend to compare treatment with metformin for six months, versus placebo in pre-diabetic subjects. We will assess the surrogate markers of ageing (leukocyte telomere length and telomerase activity) and the expression of longevity genes SIRT1, p66Shc, p53 and mTOR in peripheral blood mononuclear cells (PBMCs) before and after 6 months of metformin treatment.

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