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Development of a systems biomedicine approach for risk identification, prevention and treatment of type 2 diabetes

Periodic Reporting for period 3 - T2DSystems (Development of a systems biomedicine approach for risk identification, prevention and treatment of type 2 diabetes)

Período documentado: 2019-01-01 hasta 2019-12-31

Type 2 diabetes (T2D) is a major public health problem, affecting more than 460 million individuals worldwide. In Europe, 59 million citizens suffer from diabetes and an additional 37 million have impaired glucose tolerance (IGT), annually causing 146,000 deaths before age 60 years. By 2045 the European prevalence of T2D is projected to reach 68 million, and every 5th European will have diabetes or IGT. As a result, around 8% of European healthcare budgets are assigned to diabetes care, costing at least 150 billion Euro a year. The rise in the disease prevalence is in part due to ageing; 30% of the European population is currently over 50 years of age, and this will increase to more than 40% by 2030. The increasing obesity prevalence also contributes to the T2D epidemic, with overweight and obesity rates currently ranging between 55-62% in men and 48-58% in women in Central, Eastern and Western Europe. However, most obese or elderly individuals do not develop the disease. It is now well established that failure of the pancreatic ß cells to produce sufficient insulin is the key factor that leads to the development of T2D. Understanding the complexity of this multifactorial disease has been the holy grail of diabetes research for many decades. T2DSystems was a translational project with the primary objective of bridging the gap between in vitro human islet studies and clinical studies in human subjects. The aim is to integrate cellular and medical research data, collected by the partners, with computational modelling. To this end, we will create the Translational human pancreatic Islet Genotype tissue-Expression Resource (TIGER), by compiling and expanding existing human islet biobanks and datasets from large European islet research centres. TIGER will contain genetic, functional genomic, epigenomic, transcriptomic, proteomic and metabolomic human islet data from a large number of subjects with a broad spectrum of age, sex, genome-wide genotypes and glucose tolerance. This will allow us to identify the complex pathophysiological mechanisms and markers of a spectrum of biological and cellular processes involved in ß cell failure leading to IGT and T2D.
Significant progress was achieved with the development of TIGER. Datasets provided by partners allowed the development of the database. This included the development dataset storage including, addressing specific issues associated with ownership and use of the data. Analysis of the datasets and pipeline development together with database functionality was developed. The database is publicly available at http://tiger.bsc.es/. Development will continue to increase the datasets available within TIGER and seek collaborations with other, similar European databases to provide an integrated research resource in the area of T2D. We will continnue to organise events to increase the visibility, profile and potential utilisation of TIGER.

Partners Intomics, ULB, and BSC worked on the development of a range of tools and pipelines for analysis of the TIGER datasets. The tools allow TIGER dataset analysis of RNA sequencing and protein-protein interaction studies. RNA-seq and genotype data were harmonized, quality controlled, genotypes phased and imputed. T2DSystems partners then assembled a) genetic variation effects from T2D genome wide association studies (GWAS) meta-analyses, GWAS Catalog, Variant Effect Predictor and Gnomad, b) epigenomic marks from islet DNA-methylation sites, chromatin accessibility and CHiP-seq profiles, c) annotation from Gene Ontology, lncRNAs and islet regulome, d) gene expression from normalised islet RNA-seq counts, microarrays and the Genotype-Tissue Expression database, and e) computed eQTL and allelic specific expression and created the largest regulatory variation database from human pancreatic islets. The development of additional tools will continue to allow functional and biological inter-relationships to be investigated.

Partners are characterizing the transcriptome, regulome and metabolome of human islets exposed to metabolic stresses and therapeutic agents which modify insulin secretion. Predicted molecular mechanisms of human islet dysfunction are being validated using authentic human ß cell models, including human induced pluripotent stem cells (iPSCs) that are differentiated into ß cells, coupled with state of the art genome editing technologies and cellular phenotyping. Based on these transcriptomic and cellular studies, candidate biomarkers are being selected for assay development and investigation in patient datasets. Significant and collaborative progress continues to be made with respect to the objectives in this area. Furthermore, the partners have pursued a range of activities to identify potential genetic and circulating biomarkers, including microRNAs, associated with islet cell dysfunction in humans. This has involved studies using clinically available data generated by the partner organisations and other data repositories.

The identification of rare loss of function gene variants associated with dysfunction of transcription factors, ion channels, enzymes and incretin secretion and incretin response, all essential for insulin secretion and/or response to glucose-lowering treatments, has also been investigated. The association of rare mutations with the onset of diabetes continues to be actively investigated at the present time and this work will continue. Investigation of national registers in Denmark associated with diabetes has been accessed and the data will be used to investigate inter-relationships between single gene variants and biological functionality associated with pancreatic ß cell insulin secretion during future investigations.

The consortium has been very active in the dissemination of project results with more than 60 scientific publications and presentations arising from the research that has been performed during the project. In addition, the exploitation of project results and planning for the continued support of TIGER following the end of the project has been significantly progressed to maintain the TIGER scientific and clinical resource after the end of the project.
The new knowledge obtained from this project will be used to stratify patient-specific treatments in well-characterized patient cohorts. A new molecular level understanding of T2D is a prerequisite for the development of precision medicine. While patients and different patient cohorts may differ quite profoundly from one another, our integrative approach will allow us to understand shared underlying mechanisms as well as the features that stratify patients. Understanding patient-specific disease mechanisms through data integration and mechanistic modelling will help to identify new avenues for preserving normal glucose tolerance in groups of individuals with varying risks for T2D. As such, T2DSystems will help to develop ‘P3 medicine’: healthcare that is predictive, preventive and personalised. The results of the project will significantly enhance the current state of the art and allow more effective consideration of prevention of T2D and more patient-specific treatment. The potential impact of the project on European and global healthcare economics, quality of life, and social benefits associated with even a relatively small impact associated with T2D prevention and treatment could be highly significant.