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

The action of metformin in conjunction with Insulin, the home study

Metformin improves glycemic control in poorly controlled type 2 diabetic patients. Its effects in type 2 diabetic patients who are intensively treated with insulin have not been studied. Objective: To investigate the metabolic effects of metformin, as compared to placebo, in type 2 diabetic patients who are intensively treated with insulin. Design: Randomized, controlled, double blind trial with a planned interim analysis after 16 weeks of treatment. Setting: Three outpatient clinics in regional hospitals. Results: 390 patients whose type 2 diabetes mellitus was controlled with insulin therapy. Intervention: Random assignment to placebo or metformin in addition to insulin therapy. Indices of glycemic control, insulin requirements, body weight, blood pressure, plasma lipids, hypoglycemic events, and other adverse events. 37 subjects dropped out (12 in the placebo and 25 in the metformin group). Among those who completed 16 weeks of treatment, metformin use, as compared to placebo,La Metformine améliore le contrôle glycemique pour des patients diabétique de type 2 (pd2) , mais son effet sur des patients traits régulièrement par insuline n'a pas été investigué. Cette etude a pour objectif l'étude de l'effet métabolique de la metformine,comparée à placebo, pour des pd2. traités par insuline. L'essai a été randomize, controlé versus placebo, en double aveugle et avec une analyse intermédiaire planifiée au terme de 16 semaines de traitement. Resultas: 390 patients ont été analysés. 37 sujets furent prématurément perdus. Parmi les patients ayant terminé l'essai, le groupe metformine compare à placebo, a été observe avec un contrôle glycémique amelioré (glucose quotidian 1- semaines, 7.8 vs 8.8 mmol/L, P = 0.006; moyenne HBA1C, 6.9 vs 7.6%, P<0.0001); reduction de dose nécessaire d'insuline (63.8 vs 71.3 IU, P<0.0001); reduction de poids (-0.4 vs +1.2 kg, P<0.01); et reduction de plasma LDL-cholesterol (-0.21 vs –0.02 mmol/L, P<0.01). Les incidences d'hyoglycémies f

mEos4b Photoconversion Efficiency Depends on Laser Illumination Conditions Used in PALM

International audienceGreen-to-red photoconvertible fluorescent proteins (PCFPs) are widely employed as markers in photoactivated localization microscopy (PALM). However, their highly complex photophysical behavior complicates their usage. The fact that only a limited fraction of a PCFP ensemble can form the photoconverted state upon near-UV light illumination, termed photoconversion efficiency (PCE), lowers the achievable spatial resolution in PALM and creates undercounting errors in quantitative counting applications. Here, we show that the PCE of mEos4b is not a fixed property of this PCFP but strongly depends on illumination conditions. Attempts to reduce long-lived blinking in red mEos4b by application of 488 nm light lead to a reduction of the PCE. Furthermore, the PCE of mEos4b strongly depends on the applied 405 nm power density. A refined photophysical model of mEos4b accounts for the observed effects, involving nonlinear green-state photobleaching upon violet light illumination favored by photon absorption by a putative radical dark state

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

The effect of metformin on blood pressure plasma cholesterol and triglycerides in type 2 diabetes mellitus; a systematic review

The UKPDS 34 showed that intensive treatment with metformin significantly reduces macrovascular end-points and mortality in individuals with newly diagnosed type 2 diabetes compared with intensive treatment with insulin or sulphonylurea derivatives, despite similar glycaemic control. How this should be explained is as yet unclear. We hypothesized that metformin may have a glucose-lowering independent effect on blood pressure and lipid profile. In order to test this hypothesis we systematically reviewed the literature and pooled the data obtained in a meta-analysis.Included were randomized-controlled trials in patients with type 2 diabetes mellitus and metformin treatment lasting at least 6 weeks. To identify all eligible trials we conducted electronic searches using the bibliographic databases Medline and Embase, contacted the manufacturer and checked obtained publications for cross-references.Forty-one studies (3074 patients) provided data on blood pressure and/or lipid profile. When compared with control treatment, metformin associated effects on systolic and diastolic blood pressure and HDL cholesterol were small and statistically not significant [-1.09 mmHg 95% confidence interval (-3.01-0.82), P = 0.30; -0.97 (-2.15-0.21) mmHg, P = 0.11 and +0.01 (-0.02-0.03) mmol L(-1), P = 0.50, respectively]. Compared with control treatment, however, metformin decreased plasma triglycerides, total cholesterol and LDL cholesterol significantly [-0.13 (-0.21--0.04) mmol L(-1), P = 0.003; -0.26 (-0.34--0.18) mmol L(-1), P <0.0001 and -0.22 (-0.31--0.13) mmol L(-1), P <0.00001, respectively]. We found no indications for publication bias. Of note, glycaemic control as assessed by HbA1c was better with metformin than with control treatment [-0.74 (-0.84--0.65) percentage point; P <0.00001]. When studies were subdivided into tertiles according to increasing difference in glycaemic control between metformin and control treatment, it appeared that in case of near similar glycaemic control metformin had no effect versus control treatment on triglycerides, whereas still there was a significant effect on total and LDL cholesterol.This meta-analysis of randomized-controlled clinical trials suggests that metformin has no intrinsic effect on blood pressure, HDL cholesterol and triglycerides in patients with type 2 diabetes. This drug, however, independent of its effect on glycaemia, reduces total and LDL cholesterol significantly, but the reductions in these variables are relatively small