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Investigation of interplay between multiple determinants influencing response to metformin: search for reliable predictors for efficacy of type 2 diabetes therapy

 

 

Project Title: „Investigation of interplay between multiple determinants influencing response to metformin: search for reliable predictors for efficacy of type 2 diabetes therapy”

Funding: European Regional Development Fund (ERDF), Measure 1.1.1.1 “Industry‑Driven Research”

Project Nr.: 1.1.1.1/16/A/091

Period: 1st January 2017 – 31st December 2019

Project costs: 648 235,48 EUR 

Principle Investigator: Dr. biol., Assoc. Prof. J. Kloviņš 

 

The objective of the project is to explore underinvestigated factors characterizing response to metformin with the aim to identify reliable biomarkers of efficacy and tolerability of metformin in the treatment of type 2 diabetes (T2D). One of the main activities of the project will be dedicated to the evaluation of the correlation between metformin related changes in taxonomic and functional composition of gut microbiome and response to the treatment. We will test the hypothesis that gut microbiome contributes to glucose lowering effects of metformin and the concomitant decrease in its taxonomic diversity gives rise to pathogens responsible for gastrointestinal side effects. This will be achieved by integrating data from metagenome and 16S rRNA sequencing of gut microbiome from healthy volunteers and T2D patients before and after metformin use. The same cohorts will be used to identify novel epigenetic and RNA expression signatures in humans associated with the use of metformin, that could be used to establish clinically relevant biomarkers. To understand the causality of associations observed in humans we will perform in depth characterization of metformin affected microbiome and novel pathways in mouse models. Apart from that these experiments will give an opportunity to assess the potential benefits of metformin treatment in combination with probiotics/prebiotics to prevent undesirable changes in the gut microbiome.

Proposed project will improve our understanding of mechanisms underlying efficacy and intolerance of metformin treatment. Firstly, planned activities will help to clarify the role of gut microbiome in response to metformin. Secondly, it will provide insight in epigenetic markers and their functional impact in the context of metformin use. Experiments in mice will bring the studies one step further giving an opportunity to interfere with the negative effects of metformin. Obtained information will assist improvement of algorithms for prediction of treatment outcome as well as support development of tools for increasing efficacy and tolerance of metformin treatment.

Information published: 02.01.2017.


Progress of the project

1 January 2017 - 31 March 2017

During the first quarter of the project implementation we have initiated recruitment of potential participants as well as collection of samples for characterisation of metformin induced variation in taxonomic composition of gut microbiome and determination of epigenetic profiles in white blood cells. Concurrently algorithms for high throughput sequencing data processing, including data filtering, quality control, adjustment for cofactors and other aspects of data analysis, have been under development to fit specific longitudinal design of the research project.

Information published: 31.03.2017.


Progress of the project

1 April 2017 - 30 June 2017

During the second quarter of the research implementation we have continued with selection of project specific cohorts (healthy participants, patients newly diagnosed with type 2 diabetes (T2D) and patients with a T2D duration >3 years) and collection of biosamples for investigation of factors modifying efficiency and tolerance of metformin therapy. To characterise metformin induced variation in taxonomic composition of gut microbiome, analysis of 16S rRNS gene amplicon libraries with high throughput sequencing has been initiated. Concurrently we have started sample collection and preparation for evaluation of variation in epigenetic profiles in white blood cells during treatment with metformin. To ensure high quality of data interpretation algorithms for high throughput sequencing data processing (data filtering, quality control, adjustment for cofactors, etc.) have been developed to match longitudinal design of the research project. First reports on the progress of the research project have been given in two international conferences (19th European Congress of Endocrinology, 20.-23.05; EASD-SGGD meeting "Genetics of diabetes and its role in precision medicine", 11.-13.05).

Information published: 30.06.2017.

 

Progress of the project

1 July 2017 - 30 September 2017

For investigation of factors interacting with metformin treatment in diabetics recruitment of patients (newly diagnosed patients and patients with a T2D duration >3 years) in collaboration with endocrinologists has been continued. Amplicon libraries of 16S rRNS gene V3 region derived from healthy metformin users have been processed and grouped forming in-house database for proceeding with statistical analyses. To evaluate how changes in taxonomic composition are reflected in functional profile of gut microbiome, we have started preparation of metagenomic libraries for high throughput sequencing analysis and optimisation of respective data processing workflows. Apart from investigation of interplay between gut microbiome and metformin we have continued with analysis of epigenetic variation in white blood cells of metformin users. Epigenetic profiles have been derived from 12 healthy persons taking metformin. Concurrently selection of biological candidate genes has been initiated for identification of metabolic pathways mediating effects of metformin treatment.

Information published: 29.09.2017.



Mājas lapas izstrādi finansēja ERAF 2.1.1.2. aktivitātes projekts Nr. 2010/0196/2DP/2.1.1.2.0/10/APIA/VIAA/004 "Latvijas biomedicīnas pētījumu integrācija Eiropas zinātnes telpā".