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Metformin strongly affects transcriptome of peripheral blood cells in healthy individuals
Authors
A Gupta
A Martin-Montalvo
+63 more
AC Pawlyk
AJ Garber
AR Cameron
AR Mendelsohn
BJ Quinn
C Gutzeit
CJ Currie
Claudia Miele
Davids Fridmanis
DM Rotroff
E Shikata
EM Velazquez
F Sacco
G Zhou
Group UDPS, Wellcome Trust Case Control C GoDarts
H Malinska
H Wu
I Elbere
I Radovica-Spalvina
I Tkac
IK Vila
Ilze Elbere
Ilze Konrade
Ilze Radovica-Spalvina
Ineta Kalnina
Ivars Silamikelis
J Fadlallah
J Guo
J Padilla
JA Johnson
Janis Klovins
JD Hunter
Jekaterina Aladyeva
JEOTP P
JH Choi
JL Dixon
K Zhou
KA Jablonski
L Chen
L Trapani
Laura Ansone
M Asadbegi
M Zhang
MD Young
MG Wulffele
MN Cook
Monta Ustinova
MS Lee
MY El-Mir
N Niu
PJ Pentikainen
RA Miller
S Bruno
SE Kahn
SS Udhane
T Dayeh
T Tang
V Rovite
Valdis Pirags
Vita Rovite
X Zhou
YaH Benjamini
Z Xiao
Publication date
1 January 2019
Publisher
'Public Library of Science (PLoS)'
Doi
Cite
Abstract
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
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