Mutations in the Insulin Gene Can Cause Neonatal Diabetes

Ten previously unknown mMutations in the insulin gene can cause permanent neonatal diabetes, an unusual form of type 1 diabetes that affects very young children and results in lifelong dependence on insulin injections, report researchers from the University of Chicago and Peninsula University (Exeter, UK) in Sept. 18, 2007, issue of the Proceedings of the National Academy of Sciences, published early online.

Although abnormal insulin has been associated with milder cases of type 2 diabetes since the discovery of "insulin Chicago" in 1979, this is the first time that an insulin mutation has been connected to severe diabetes with onset early in life.type-1 diabetes.

The researchers describe the10 mutations, found in 221 patients from 16 families., and show how several of the mutations alter the way the protein folds, disrupting insulin synthesis. They suspect that the mutations alter the way insulin folds during its synthesis. TThey suggest that these improperly folded proteins interfere with other cellular processes in ways that eventually kill the cells that produce insulin.

"This is a novel and potentially treatable cause of diabetes in infants," said study author Louis Philipson, MD, PhD, professor of medicine at the University of Chicago. "It's exciting because each of these patients has one normal insulin gene as well as one mutated gene. If we could detect the disease early enough and somehow silence the abnormal gene, or just protect insulin-producing cells from the damage caused by misfolding, we might be able to preserve or restore the patient's own insulin production."

The effort to learn more about possible genetic causes of neonatal diabetes followed a flurry of publicity last September. Philipson and colleagues at the University of Chicago - using a protocol developed by co-author Andrew Hattersley, MD, Professor of Molecular Medicine at Peninsula University - were able to wean a young diabetes patient with a known, treatable mutation in an ion channel protein essential for insulin secretion, off of insulin. This was one of the first such cases in the United States.

Media coverage of that case and outreach by the Juvenile Diabetes Research Foundation stimulated parents of other children diagnosed as infants with type-1 diabetes to contact one of the two centers to request genetic testing. Testing at the University of Chicago uncovered more than a dozen patients with the same treatable mutation.

The publicity also brought calls from the families of more than 870 patients who had been diagnosed with diabetes at less than one year of age but who, as it turned out, did not have a known mutation. Many [all?] of these children lacked the antibodies usually present in patients with typical type-1 diabetes, which is typically caused by an immune assault on the insulin-producing pancreatic beta cells.

In one family with four affected individuals, tests for known mutations were negative. A combination of linkage studies and candidate-gene testing, however, traced the problem to an abnormal insulin gene. Further tests identified a total of 10 different insulin-gene mutations in patients from 15 other families.