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

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 (log 2 FC 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.

Metformin Strongly Affects Gut Microbiome Composition in High-Fat Diet-Induced Type 2 Diabetes Mouse Model of Both Sexes

“…10,11). It has been shown that metformin exerts its effects on the microbiome already in the first 24 hours ( 10 )⁠ and that the alterations in the gut microbiome could be related to the metformin-induced immune response ( 13 )⁠.…”

Acute Effects on the Human Peripheral Blood Transcriptome of Decompression Sickness Secondary to Scuba Diving

“…To ensure that the observed transcriptomic changes are a faithful representation of the DCS state, care was taken to minimize interindividual differences amongst the divers selected for this study. The peripheral blood transcriptome is known to broadly reflect the combined effects of pharmacotherapy, chronic disease, and environmental exposures such as smoking ( Lampe et al, 2004 ; Liu Y. et al, 2015 ; Beretta et al, 2020 ; Ustinova et al, 2020 ). While these factors are integral components of many human studies, they can cause confounding in gene expression experiments.…”

Recent Multiomics Approaches in Endometrial Cancer

“…The study of the transcriptome finds great application in studies aimed at searching for new molecular markers and therapeutic targets. They involve numerous human diseases, including neurological disorders such as chronic pain [19], multiple sclerosis [20], diabetes [21], cardiovascular disease [22], cancers, and their response to treatment [23]. Microarrays and high-throughput RNA sequencing are of great importance, as they rapidly provide a huge amount of data on the processes or organisms under study [24].…”