Metformin strongly affects transcriptome of peripheral blood cells in healthy individuals

Funding Information: The study was supported by the European Regional Development Fund under the project ?Investigation of interplay between multiple determinants influencing response to metformin: search for reliable predictors for efficacy of type 2 diabetes therapy? (Project No.: 1.1.1.1/16/A/091, https://ec.europa.eu/regional_policy/en/funding/ erdf/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank all the volunteers for their participation and acknowledge the Genome Database of the Latvian Population for providing biological material and data. Publisher Copyright: © 2019 Ustinova et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Metformin is a commonly used antihyperglycaemic agent for the treatment of type 2 diabetes mellitus. Nevertheless, the exact mechanisms of action, underlying the various therapeutic effects of metformin, remain elusive. The goal of this study was to evaluate the alterations in longitudinal whole-blood transcriptome profiles of healthy individuals after a one-week metformin intervention in order to identify the novel molecular targets and further prompt the discovery of predictive biomarkers of metformin response. Next generation sequencing-based transcriptome analysis revealed metformin-induced differential expression of genes involved in intestinal immune network for IgA production and cytokine-cytokine receptor interaction pathways. Significantly elevated faecal sIgA levels during administration of metformin, and its correlation with the expression of genes associated with immune response (CXCR4, HLA-DQA1, MAP3K14, TNFRSF21, CCL4, ACVR1B, PF4, EPOR, CXCL8) supports a novel hypothesis of strong association between metformin and intestinal immune system, and for the first time provide evidence for altered RNA expression as a contributing mechanism of metformin’s action. In addition to universal effects, 4 clusters of functionally related genes with a subject-specific differential expression were distinguished, including genes relevant to insulin production (HNF1B, HNF1A, HNF4A, GCK, INS, NEUROD1, PAX4, PDX1, ABCC8, KCNJ11) and cholesterol homeostasis (APOB, LDLR, PCSK9). This inter-individual variation of the metformin effect on the transcriptional regulation goes in line with well-known variability of the therapeutic response to the drug.publishersversionPeer reviewe

Discontinuation of metformin in Type 2 Diabetes patients treated with Insulin,

Metformin added to insulin therapy in type 2 diabetic patients improves glycaemic control and decreases the required daily dose of insulin (DDI). Metformin should be discontinued if cardiac, hepatic or renal failure develops. We examined whether glycaemic control can be maintained after metformin cessation. We included 45 type 2 diabetic patients treated with insulin plus metformin, and 45 matched controls treated with insulin only. During 12 weeks we assessed glycaemic control every two weeks and, if necessary, adjusted the insulin dosage. Results: In the group in which metformin was discontinued, DDI increased from 67.9 ± 22.9 to 92.2 ± 29.4 IU (p<0.00I) leaving glycaemic control unchanged. In type 2 diabetic patients treated with insulin plus metformin, glycaemic control can be maintained after discontinuation of metformin by increasing the DDI substantially (20 to 36%) during application of an intensified treatment protocol.Metformin supplémentaire à la thérapie d'insuline dans le type 2 patients diabétiques améliore le controle glycémique et diminue la dose quotidienne exigée de l'insuline (DDI). Metformin devrait être discontinué si cardiaque, hépatique ou l'échec rénal se développe. Nous avons examiné si le controle glycémique peut être maintenu après cessation de metformin. Nous avons inclus 45 le type 2 patients diabétiques traités avec l'insuline plus le metformin, et 45 ont assorti des commandes traitées avec l'insuline seulement. Pendant 12 semaines nous avons évalué le controle glycémique toutes les deux semaines et, au besoin, avons ajusté le dosage d'insuline. Résultats : Dans le groupe dans lequel le metformin a été discontinué, DDI accru 67.9 du ± 22.9 92.2 au ± 29.4 unité internationale