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The causes of hyperglycaemia in the face of rising obesity

Final Report Summary - GLUCOSEGENES (The causes of hyperglycaemia in the face of rising obesity)

ERC funding for GLUCOSEGENES has resulted in some important advances in understanding susceptibility to high glucose levels and type 2 diabetes. The research has resulted in an improved understanding of how two people of the same age, sex, ethnicity, and, critically, body mass index, can have very different risks of type 2 diabetes. Advances include: i) discovering that most common human alleles associated with better insulin sensitivity are associated with higher, not lower body fat. Collaborations made possible by GLUCOSEGENES led to a likely explanation for this apparent “favourable adiposity” paradox – that these alleles were associated with higher subcutaneous but lower liver fat; ii) that genetic variants altering BMI have stronger effects in some situations – for example in people who are from more deprived backgrounds. We have provided a more robust analytical framework for testing such gene x environment interactions and published software to help advance this field; iii) by performing the largest genome wide association study of intravenous glucose tolerance tests, we have established that most variants associated with type 2 diabetes have primary direct effects on the beta-cell; iv) we have performed some of the largest “recruit-by-genotpe” studies to study the detailed islet secretory function of diabetes associated variants. These studies include those of 51 people carrying the low frequency variant in the CCND2 gene associated with a strong protective effect on type 2 diabetes – and age, sex and BMI matched controls. This study did not reveal a difference but has resulted in the set up of sophisticated tests of insulin secretion and their measurement in relatively large numbers of people in Exeter, and we are now using glucose potentiated arginine stimulated insulin secretion tests to assess the role of genetic risk scores in different aspects of insulin secretion; v) the use of Mendelian randomisation to understand in more detail the causal relationship between diabetes risk factors and outcomes. Notably we have established the novel principle of using the alleles associated with higher adiposity but lower risk of metabolic disease to “uncouple” higher fat mass from it’s adverse metabolic risk factors. This concept is important for many “non-metabolic” diseases such as osteoarthritis, gastro-oesophageal disease and depression, where the mechanical or psychological effects of the excess weight may be the primary cause of disease rather than adverse inflammation, lipids or insulin levels. We have used this approach to provide evidence that higher adiposity without it’s adverse metabolic effects has equally strong effects on depression as higher adipoty with it’s adverse metabolic effects. This result is more consistent with depression being caused by the psychological effects of excess weight rather than the metabolic or inflammatory effects. Finally GLUCOSEGENES has resulted in wide dissemination of data and software as well as high impact publications. Data funded by GLUCOSEGENES is publically available at established portals such as those at the Accelerating Medicines Partnership and open source software is available at the github site.