Insulin-dependent diabetes (type 1 diabetes) results from a severe lack of insulin, due to the destruction of insulin-producing beta cells in the pancreas. The beta cells are destroyed by the body’s own immune defences, which mistakenly treat them as ‘foreign’ rather than ‘self’ – a so-called autoimmune reaction. The disease is usually diagnosed between the ages of 2 and 16, and affected individuals need daily insulin injections to keep the disease at bay.

As with many diseases, type 1 diabetes is influenced both by genetics and the environment. Great strides have been made recently in the genetic understanding of diabetes, and a unique funding collaboration between the Wellcome Trust and the US-based Juvenile Diabetes Research Foundation (JDRF) will greatly accelerate the identification of genes involved in the most severe form of childhood diabetes, and in the complications that can develop later in life – such as kidney failure, blindness and heart disease. These discoveries should ultimately lead to novel therapeutic targets and preventative strategies.

The Wellcome Trust and the JDRF are providing grants of around £10 million each, over five years, to set up a new Diabetes and Inflammation Laboratory under the leadership of Professor John Todd. The new laboratory will be housed within the existing Wellcome Trust Centre for Molecular Mechanisms in Disease in Cambridge. According to Professor Todd, one of the main aims of the grant is to help identify the genetic differences that predispose some, but not others, to insulin-dependent diabetes. This knowledge will eventually permit a ‘pharmacogenetic’ approach to its treatment – one that will exploit underlying genetic variability to tailor treatments to individuals.

Because of the complex nature of diabetes, Professor Todd’s team is using a number of approaches to explore its origins. The programme will take advantage of a mouse model of the disease, recent advances in human and mouse genome sequencing projects, and a map of genetic variations called single nucleotide polymorphisms (SNPs). SNPs act as ‘landmarks’ on chromosomes, enabling researchers to track which areas of the genome tend to be associated with diabetes – a clue to the presence of diabetes-causing genes. It will also make use of huge collections of diabetic families to provide enough statistical power to pinpoint key genes.

According to Professor Todd, the success of the Human Genome Project prompted him to apply for the joint funding: “This was an opportunity to crack the genetics of type 1 diabetes.” Bob Goldstein, Chief Executive of the JDRF, encouraged Professor Todd to submit a grant application, and Professor Todd asked the JDRF if they would be interested in collaborating with the Wellcome Trust, who had been funding much of his research for several years. Shortly before Christmas 1999, Professor Todd and Dr Goldstein met with Mike Dexter, the Trust’s Director, and Trust staff in London.

“In January, we started working very fast indeed,” says Professor Todd, encouraged by this first meeting. It was decided that all administration and peer review would be overseen by the Trust and at the end of June – on Professor Todd’s birthday – the proposal was accepted in principle. “Some of us are still recovering from the speed that the application has gone through; it was an enormous effort. But if we can get the planning in place by Christmas, it will mean that the grant will have been conceived, written, awarded and established in 12 months.”

Professor Todd’s interest in genetics and mechanisms of type 1 diabetes began with his postdoctoral research at Stanford University, where in 1987 he discovered that sequence variation in a gene within the major histocompatibility complex (MHC) predisposes to type 1 diabetes. The gene is thought to influence the development of at least 90 per cent of cases of type 1 diabetes.

When Professor Todd moved to Oxford in 1988, he combined forces with Linda Wicker and Larry Peterson from Merck Research Laboratories in the USA to establish a mouse model of type 1 diabetes. These so-called nonobese diabetic (NOD) mice are now used by researchers throughout the world. The two teams found that alterations in the MHC in these animals, as in humans, were not sufficient for disease; instead, a number of genes must act together.

Professor Todd and Dr Wicker have now bred NOD mice with single or multiple genetic differences, allowing the effects of individual genes or groups of genes to be studied in minute detail. The new grant will allow Dr Wicker to take forward these studies with Professor Todd in Cambridge. They will also take advantage of the fact that the chromosomal locations of genes in mice can be used to identify the equivalent genes in humans. At least three regions of the human genome have been firmly implicated in diabetes. Of these, two – the MHC region of chromosome 6 (called IDDM1) described above, and a variant of the insulin gene (IDDM2) – have been relatively well characterised. Professor Todd believes that the variation in the insulin gene affects the production of an immature form of insulin in the thymus, where immune cells learn to distinguish ‘self’ from ‘foreign’. This abnormal production may prevent the immune system from learning that the insulin is ‘self’, causing immune cells to attack insulin-producing beta cells.

Recent results from his team suggest that a third gene region, designated IDDM12, normally functions to regulate the immune system. Professor Todd believes he is only a matter of months away from identifying the gene located in this region and thereby identifying another potential therapeutic target. The new grant will allow the Cambridge team, in collaboration with others, to track down at least three additional genes likely to be linked to diabetes.

Genes are not the sole explanation for type 1 diabetes, however. “From an environmental perspective, my view is that infection and diet are extremely important factors in type 1 diabetes, and their effects are probably at least as complex as those of the genes. These non-genetic factors modify the diabetes potential of the genetic background. If environmental factors responsible for diabetes can be identified and controlled, and the specific genetic defects can be tackled with drugs, we could make a significant impact on the incidence of the disease.”

Once genes are identified, Professor Todd can take advantage of the multidisciplinary environment at the Centre. “We have expertise here in a number of different areas – from genetics, biochemistry, crystallography and cell biology, through to in vivo imaging and physiology – and we’ll use all of these forces to crack this thing.”

See also

• Juvenile Diabetes Research Foundation Announcement of funding collaboration (press release)

External links

• Wellcome Trust Centre for Molecular Mechanisms in Disease
• Professor Todd at the Wellcome Trust Centre for Molecular Mechanisms in Disease: Research interests
• British Diabetic Association