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Genetics of type 2 diabetes

Over three million people in the UK are diagnosed with diabetes, a figure set to rise. A further 850 thousand remain undiagnosed. Around 90% of these cases have type 2 diabetes. Although treatments are available, they are not always effective. There is therefore a pressing need to improve our understanding of this condition.

Type 2 diabetes develops when the body becomes insensitive, or resistant, to the action of insulin and when the ability of the body to produce more insulin to counter this resistance begins to decline. Insulin normally regulates our blood sugar level by acting upon many tissues, including muscle, liver and fat, to control how much sugar is stored or produced and ensure the amount of sugar in the blood is kept constant. In type 2 diabetes, these tissues no longer respond to insulin as well as they should, so the regulation of blood sugar goes awry.

While type 2 diabetes usually occurs in people over the age of 40, there are risk factors such as obesity that increase the likelihood it will develop at a younger age. Diabetes causes significant mortality and morbidity as a result of complications that develop over prolonged periods of time. By the time they are diagnosed, around half of patients show complications such as reduced vision, kidney problems and cardiovascular disease. As a result diabetes costs the UK NHS an estimated £27 million per day. Treatment for diabetes mitigates these complications but there are a limited number of drugs available with varying efficacy and therefore there is a need for new and better treatments.

Examination of human genes associated with type 2 diabetes and obesity

A major objective of our work is the functional identification and characterisation of genes from loci identified in human genome wide association (GWA) studies for diabetes and obesity. Since 2007, human GWA studies have identified numerous genetic loci implicated in type 2 diabetes, obesity and various metabolic traits. The challenge now is to identify and functionally characterise this resource of human susceptibility genes underlying GWA loci. 

Novel insights into mechanisms underlying disease can come from genetic approaches such as the mapping and identification of genetic loci that give rise to diabetes or related metabolic traits. The characterization of mutations and polymorphisms in particular genes and pathways linked to disease traits can then yield novel information about basic biology and physiology that may ultimately be translatable for therapeutic benefit.

Our strategy is to select candidate genes supported by data from human genetics collaborators and make mouse models for their functional analysis. These models include conditional overexpression, conditional knockout, point mutation alleles and alleles generated by genome editing technologies. We conduct detailed in vivo metabolic analysis of these models and in vitro experiments using tissues from them in order to understand the function and mechanism of action of genes involved in diabetes and obesity.

Identification and investigation of new type 2 diabetes mouse models

A second objective of our work is the identification of novel genes and pathways for diabetes and diabetic complications. Three approaches are being taken:

  1. Characterising models of insulin resistance, insulin secretory defects and obesity from past work. Once genes are cloned they are investigated in more detail to determine their function, particularly where their role in diabetes was not previously known.
  2. Exploiting new diabetes genes identified by the International Mouse Phenotyping Consortium (IMPC).
  3. Continued screening for new models from the Harwell Ageing Screen to allow later onset metabolic phenotypes and complications of diabetes to develop. We are phenotyping for impaired glucose tolerance, diabetes, obesity, energy metabolism, dyslipidaemia and fatty liver disease. Selected lines undergo more detailed physiological and molecular phenotyping, as well as mapping and cloning of the underlying mutations.

Our overall aim is to develop new mouse models for type 2 diabetes and its main risk factor obesity, which will allow the identification of new genes and/or pathways. This will help further the understanding of the basic biology and physiology of type 2 diabetes, largely conserved between mouse and human, and ultimately identify new targets for therapeutic intervention.