Genetics of Type 2 Diabetes
Group Leader : Roger Cox
In the UK there are about 2.9 million people (2011 figures) diagnosed with diabetes - that is 4.45% of UK adults. Globally the estimated prevalence for 2011 is 366 million. Around 90% of diabetes is type 2 and develops when there are problems with insulin secretion and insulin action (insulin resistance). Type 2 diabetes usually occurs in people over the age of 40, although, in some particular higher risk populations and with increasing obesity (a key risk factor for type 2 diabetes) the disease is often being found in younger people. Diabetes can reduce life expectancy and by the time of diagnosis about half of people show signs of complications such as eye, kidney and cardiovascular disease. Current treatments can reduce the risks of complications significantly. Key statistics on diabetes can be found in the Diabetes Atlas, Fourth Edition (2009) at: http:// www.diabetesatlas.org and in regular reports for Diabetes UK at: http://www.diabetes.org.uk/
Our overall aim is to develop new mouse models for type 2 diabetes that will allow the identification of key genes and/or pathways for a systematic analysis of the process of disease development and the effect of environmental factors. This may help further the understanding of the biology of diabetes and ultimately identify new targets for therapeutic intervention. Three main approaches are being used:
Over the next 5 years we are screening for new models from ENU mutagenesis G3 pedigrees (recessive and dominant) aged to 18 months in order to allow later onset metabolic phenotypes and complications of diabetes to develop. The aim is to have large enough pedigrees to map and identify genes by next generation sequencing (NGS) in one step. We are screening for impaired glucose tolerance, diabetes and its complications, obesity, bone and mineral disorders and liver disease.
A second focus is on the functional identification and characterization of genes from loci identified in human GWAS studies for diabetes and obesity. We are doing this by searching for point mutations in the Harwell ENU DNA archive and by making conditional overexpression and knockout alleles. A major programme within this is on the functional analysis of the fat mass and obesity-associated gene FTO. This is funded with a grant from the Wellcome Trust and is in collaboration with Professor Frances Ashcroft, University of Oxford. Work on other genes is underway in collaboration with other groups at the Oxford Centre for Diabetes Endocrinology and metabolism. With these and other partners we are part of the MRC mouse network consortium “Models of Diabetes and Obesity” that is nominating priority genes for the International Mouse Phenotyping Consortium (IMPC) work at Harwell and capitalising on the primary data from these knockout mice.
Finally we are characterizing new models of obesity, insulin resistance and secretion, arising from past work, which includes detailed physiological and molecular phenotyping, and mapping and cloning of the underlying mutations. Once genes are cloned they are investigated in more detail to determine their function particularly where their role in diabetes was not previously known.