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

Periodic Reporting for period 1 - T2DSystems (Development of a systems biomedicine approach for risk identification, prevention and treatment of type 2 diabetes)

Reporting period: 2016-01-01 to 2017-06-30

Type 2 diabetes (T2D) is a major public health problem, affecting more than 400 million individuals worldwide. In Europe, 55 million citizens suffer from diabetes and an additional 66 million have impaired glucose tolerance (IGT), causing 630,000 deaths each year. By 2030 the European prevalence of T2D is projected to reach 150 million, meaning that every 5th European will have diabetes or IGT. As a result, around 28% of European healthcare budgets are assigned to diabetes care, costing at least 78 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 is 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 >1400 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.
Since commencing the project, significant progress has been achieved by the consortium with the development of TIGER (work package 1). Datasets have been provided by partners within the consortium to allow the development of the database. This has included the development of how the datasets will be stored and addressing specific issues associated with ownership and use of the data. Analysis of the datasets and development of pipelines has progressed and initial testing of the database functionality has commenced. The database has demonstrated functionality with the current datasets and pipelines. The next phase of development will be to increase the datasets available within TIGER and also to start incorporating published datasets from the partners to increase the visibility, profile and potential utilisation of TIGER across the scientific community.

In parallel to the development of TIGER, progress has been made with the development of the web-based TIGER portal. The design and functionality has been developed and will be further enhanced and tested during the next reporting period. A visual identity for the TIGER web-portal has been established and this will be transferred to the main project website. This will allow the TIGER visual identity to be clearly implemented across all aspects of the T2DSystems project, and will allow the scientific community to become aware of this new tool.

Partners at Intomics, ULB, ICL and BSC have been working in close collaboration on the development of a range of tools and pipelines to facilitate the analysis of data held within the TIGER database (work package 2). Initial use of the tools has been associated with studies of datasets submitted to BSC by the partners, analysis of RNA sequencing and protein-protein interaction studies, and the investigation of the use of the inBio Map for protein-protein interaction studies. The development of these initial tools will be further augmented as more datasets are added to the TIGER resource and the functional and biological inter-relationships are investigated.

Partners working within work package 3 have been making efforts to extend the characterization of the transcriptome, regulome and metabolome of human islets exposed to therapeutic agents which modify their ability to secrete insulin. Predicted molecular mechanisms of human islet dysfunction are being validated using authentic human ß cell models, including human induced pluripotent stem cells (iPSCs) coupled with state of the art genome editing technologies and cellular phenotyping. Based on these transcriptomic and cellular studies, candidate biomarkers will be selected for assay development and investigation in human patient datasets. Significant progress has been made by various of the groups with respect to the objectives of work package 3 and the partners have collaborated in a number of areas and studies. Personnel have been transferred between the partners to facilitate collaboration and training.

The partners undertaking work package 4 have pursued a range of activities to identify potential biomarkers associated with islet cell dysfunction in humans. This has involved a range of investigations and studies using clinically available data generated by the partner organisations and other data repositories.

Progress within work package 5 has focussed on the identification of rare mutations associated with the loss of function associated with dysfunction of ion channels essential for insulin secretion. The association of rare mutations with the onset of diabetes is being 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 mutations and biological functionality associated with pancreatic ß cell insulin secretion.
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.
TIGER web portal front page