Whole-blood transcriptome profiling reveals signatures of metformin and its therapeutic response

Monta Ustinova, Laura Ansone, Ivars Silamikelis, Vita Rovite, Ilze Elbere, Laila Silamikele, Ineta Kalnina, Davids Fridmanis, Jelizaveta Sokolovska, Ilze Konrade, Valdis Pirags, Janis Klovins (Coresponding Author)

Research output: Contribution to journalArticlepeer-review

Abstract

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 volunteers with type 2 diabetes in vivo. The 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 a 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), that is 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 metformin in patients with type 2 diabetes mellitus.

Original languageEnglish
Article numbere0237400
JournalPLoS ONE
Volume15
Issue number8 August
DOIs
Publication statusPublished - Aug 2020

Field of Science

  • 1.6 Biological sciences

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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