Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response
Metformin, a biguanide agent, is the first-line treatment for type 2 diabetes mellitus due to its glucose-lowering effect. Despite its wide application in the treatment of multiple health conditions, the glycemic response to metformin is highly variable, emphasizing the need for reliable biomarkers.   We chose the RNA-Seq-based comparative transcriptomics approach to evaluate the systemic effect of metformin and highlight potential predictive biomarkers of metformin response in drug-naïve type 2 diabetes patient volunteers in vivo.  Longitudinal blood-derived transcriptome analysis revealed metformin-induced differential expression of novel and previously described genes involved in cholesterol homeostasis (SLC46A1 and LRP1), cancer development (CYP1B1, STAB1, CCR2, TMEM176B) and immune responses (CD14, CD163) after administration of metformin for three months. We demonstrate for the first time transcriptome-based molecular discrimination between metformin responders (delta HbA1c = 1% or 12.6 mmol/mol) and non-responders (delta HbA1c < 1% or 12.6 mmol/mol) determined by expression levels of 56 genes, explaining 13.9% of the variance in the therapeutic efficacy of the drug.  Moreover, we found a significant upregulation of IRS2 gene (log2FC 0.89) in responders compared to non-responders before the use of metformin. Finally, we provide evidence for the mitochondrial respiratory complex I as one of the factors related to the high variability of the therapeutic response to metforminin patients with type 2 diabetes mellitus. Overall design: Longitudinal RNA-Seq data of venous blood samples collected from 17 type 2 diabetes mellitus patients in two consecutive time points:before administration of metformin, after 3 months of metformin therapy.