Type 1 diabetes and the insulin VNTR allele 8/3/04. By John Pickrell A variable region of DNA near to the insulin gene has a marked influence on the risk of getting type 1 diabetes.

Type 1 diabetes is a classic example of a complex disease caused by the interaction of environmental factors with many genes. Finding genes for diseases such as diabetes is challenging because some occur almost as frequently in disease sufferers as in healthy people.

Type 1 diabetes accounts for about a tenth of all cases of diabetes and is the most serious form of the disease. Also known more descriptively as juvenile-onset or insulin-dependent diabetes, type 1 diabetes is most commonly diagnosed at the age of 12.

In type 1 diabetic patients, production of insulin is severely reduced following a destructive autoimmune response that annihilates the insulin-producing beta cells in the pancreas. The body's own immune response is directed against a number of beta-cell proteins, notably insulin itself, the insulin precursor preproinsulin, and an enzyme called glutamic acid decarboxylase.

The insulin gene

In the mid-1980s, it had been suggested that DNA close to the insulin gene influenced the risk of getting type 1 diabetes. It would take another ten years and the development of a relatively comprehensive set of genetic markers before John Todd's group at the University of Cambridge, in tandem with colleagues in Florida and Canada, confirmed this type 1 diabetes-associated polymorphism to be a region of DNA, close to the insulin gene, called a VNTR (variable number of tandem repeats). As its name suggests, this region is made up of a small sequence of DNA repeated many times.

In Europeans, there are two main categories of VNTR alleles: those with fewer than 50 repeats, and those with more than 200 repeats. Studies have shown that people with only the low number repeat are more likely to have type 1 diabetes than those with at least one higher number allele.

"Carrying a protective allele gives you at least 50 per cent protection from the disease," says Professor Todd. "It's a rather dramatic effect."

The variability in the length of the repeat is important in the way autoimmunity arises or is prevented. The VNTR plays a role in regulating the expression of the insulin gene in the thymus, a gland behind the breastbone in which the immune system 'learns' to distinguish foreign matter from self.

Insulin genes with long repeats are expressed at two to three times higher levels than those with short repeats. That matters because, if more of a protein is produced in the thymus, it will increase the chances that the thymus will recognize it as a self protein. When the thymus encounters a T cell that recognizes a self antigen, it sends a signal that, in effect, kills or deletes the T cell.

Thus, the long VNTR may offer protection against autoimmunity by stimulating insulin expression in the thymus and increasing the body's awareness that insulin is one of its own proteins.

Links

Professor John Todd: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory , University of Cambridge