Our group has developed a growing interest in neonatal diabetes, a very rare form of diabetes caused by mutations that affect insulin-secreting cells and requiring multiple daily insulin injections. One group of these mutations can be treated with pills, allowing patients who have what looks like type 1 diabetes to be transferred off of insulin.
We have been able to wean about 15 patients away from insulin in the past year, a dramatic and gratifying experience and a spectacular example of the promise of molecular medicine.
We suspect there are 1-2,000 people in the United States with this form of neonatal diabetes who could benefit from the same treatment if precisely diagnosed and treated relatively early in life.
The search for patients with those mutations recently led us to a series of new genetic abnormalities that can cause diabetes in infants. We found that mutations in the insulin gene can cause neonatal diabetes that is indistinguishable, without specific genetic testing, from type 1 diabetes.
These mutations are often inherited. While most of the parents in those cases do not have measurable insulin secretion, children with this form of diabetes do produce insulin. These mutations interfere with normal insulin folding, however, which causes severe stress in the cell. Over time, this can kill the insulin-producing cells.
We have two existing mouse models of insulin gene mutations. These are similar, but not identical, to the human mutations, except that rodents have four copies of genes encoding insulin, and humans have only two. In mice and in humans, however, a mutation in just one copy of the gene can cause the disease, a dominant effect.
This is the first known non-autoimmune genetic model of beta cell death in humans -- a kind of Type 1b diabetes. These mice provide an excellent opportunity to test drugs that could ameliorate stress in beta cell function and encourage the growth of new beta cells. Thus, regeneration and protection of beta cells will be tested in these humans with insulin mutations once the compounds are evaluated in cells in the laboratory and in the mouse models.