Identification of various pathogenic mechanisms of type 2 diabetes development using patient specific cell models
Funding: Latvian Council of Science
Project number: 343/2012
Project manager: Dr.med.V.Pīrāgs
Type 2 diabetes mellitus (T2D) is a heterogeneous group of metabolic and endocrine disorders associated with secretory dysfunction of the pancreatic islet cells, reduced islet mass and impaired insulin action resulting in chronic hyperglycaemia and typical micro- and macrovascular complications. Development of T2D triggered in consequence of complex interaction of lifestyle factors, obesity and genetic risk factors with deleterious impact on glucose metabolism and insulin signalling. Recent discoveries have advanced our understanding of type 2 diabetes genetics and pathogenic mechanisms, however many questions still remain. Furthermore existing therapies often fail to reach satisfactory results.
Studies based on cell lines bearing patient specific genotype help to learn more about the genes and their interactions with environmental factors that lead to the disease or in contrary which factors protect some highly predisposed individuals from developing it. These cell lines can be used to evaluate effects of genotype on effectiveness of therapy.
The aim of the project
The aim of the current project is to develop new patient-specific cell models for type 2 diabetes (T2D) in order to study genes and pathways involved in the pathogenesis of the disease.
The specific objectives of our research are the following:
To recruit participants in three groups, patients with T2D or MODY and subjects with normal glucose tolerance and collect adipose tissue and blood samples along with biochemical measurements, genotypes, information on health and disease history in family.
To isolate adipocyte derived stem cells from obtained tissue samples and differentiate those cells to both adipocytes and insulin-producing cells.
To perform transcriptome sequencing and mRNA profiling in adipocytes and insulin-producing cells under normal and stress conditions caused by glucotoxicity, lipotoxicity or inflammation.
To analyse genetic variation in the genes that according to expression data may be involved in specific metabolic pathways and to evaluate possible impact of these variants on the functions and vitality of the cells.
To perform exome or whole genome sequencing for participants with phenotypes of particular interest (derived cell lines showing extreme phenotypes or distinct transcription patterns) and for their family members.
To assess the effects of widely used drugs such as thiazolidinediones, sulfonylureas and GLP-1 agonists in differentiated patient specific adipocytes or insulin-producing cells and analyse possible modifying impact of genetic factors.
Studies in the cell lines bearing patient specific genotypes will provide information about the significance of specific genetic factors and their combinations in forming cell response to environmental stress and medicaments. Information on gene expression patterns specific for cell with particular genetic background in controlled environment may help to reveal novel signalling pathways implicated directly or indirectly in modelling cell response. Testing of the antidiabetic drugs for toxicity and efficacy in the developed cell lines will allow detection of genetic factors altering the therapy. Together obtained data may add to the current knowledge of T2D pathogenesis and enable to integrate data on numerous genetic markers associated with glucose metabolism with functional studies to decode mechanisms of the metabolic disease.