Effect of metformin on metabolomic and circulating miRNAs profile in type 2 diabetes mellitus patients: a pilot analysis of sex differences

The impact of sex on metformin (METF) activity has been largely overlooked. This pilot study investigates sex influences metabolic and microRNA (miRNAs) profiles in diabetic patients treated with METF therapy compared to those not treated with METF. Fifty-six outpatients with type 2 diabetes mellitus (29 men and 27 women), Caucasian, non-smokers, normotensive, normolipidemic, in good metabolic control, and free from diabetic complications were recruited. They were divided into two groups, drug-naïve and METF-treated, and stratified by sex. Serum samples were collected and analyzed for amino acids (AA) and acylcarnitines (AC), advanced glycation end products (AGEs), malondialdehyde (MDA), and 8 selected circulating miRNAs. Women treated with METF (W-METF) showed lower MDA than the W-drug-naïve, while AGEs were reduced in both the W-METF and men treated with METF (M-METF). In the W-METF, five miRNAs were upregulated compared to the W-drug-naïve, whereas three miRNAs were upregulated in the M-METF group compared to the M-drug-naïve. AA and AC are sex-dependent: W-METF showed more differences than W-drug-naïve, while men had fewer changes. METF impacted women's AC profiles more, with 23 out of 39 AC being significantly reduced, compared to only 4 AC being reduced in men. METF amplifies sex differences increasing their number from 11 in the drug-naïve patients to 39 in the METF-treated patients. MiR-223-3p was upregulated only in W-METF. This pilot study highlights that METF induces significant sex-dependent changes in the blood metabolome and 8 circulating miRNAs, paving the way for large-scale studies and suggesting that METF therapy could be personalized based on sex.