Single gene mutation may be behind type 1 diabetes for minority of patients

Genetic analysis of a family predisposed to type 1 diabetes (T1D) has uncovered the first kind of T1D to be caused by a single gene mutation.

The study links an inherited mutation of SIRT1 to the destruction of pancreatic beta cells by the immune system. Pancreatic beta cells are important for insulin production and insufficient production of insulin, a hormone that regulates blood sugar levels, is the central feature of T1D.

The previously undocumented mutation - a single-letter change in the gene code - was discovered in a family where four members were diagnosed with T1D, and another with ulcerative colitis, an autoimmune disease.

Professor Marc Donath of Basel University Hospital in Switzerland, who led the research, said the discovery 'could allow us to understand the mechanism responsible for the disease and may open up new treatment options'.

Experiments on mice by Professor Donath's team suggest that the SIRT1 mutation causes the insulin-producing cells to release higher amounts of inflammatory chemicals, including nitric oxide, cytokines and chemokines. Excessive production of these immune modulators is known to lead to T1D and other autoimmune diseases.

The mutation uncovered in the paper is thought to exist in only a small number of people with T1D. However, Dr Patricia Kilian, director of the beta cell regeneration programme at the Juvenile Diabetes Research Foundation,  which funded the study, commented: 'Whilst the change in the genetic makeup within this family with T1D is rare, the discovery of the role of the SIRT1 pathway in affecting beta cells could help scientists find ways to enhance beta cell survival and function in more common forms of the disease'.

Dr Siri Atma Greeley at the University of Chicago, who was not involved in the study, gave a somewhat more sceptical view to Medill Reports. He said that 'how many other people with diabetes or other  autoimmune diseases will have mutations in this gene [...] remains entirely unknown'. He also cautioned that T1D has been linked to other genetic mutations.

To follow on from their study, Professor Donath's group are planning to create a mouse model of T1D with the specific SIRT1 mutation identified in this paper. The team also hope to begin a clinical trial to assess whether SIRT1 activators can help prevent the destruction of beta cells by the immune system.

The study was published in the journal Cell Metabolism.