Research Update

Research Hones in on Detection, Treatment of Rare Forms of Type 1

Last month, researchers from the University of Chicago’s Comprehensive Diabetes Center and Peninsula University (Exeter, UK) published research in the Proceedings of the National Academy of Sciences that discussed ten previously unknown mutations in the insulin gene that 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. In the first of a series of articles exclusively for the dLife community by University of Chicago Hospital clinicians and researchers, Dr. Lou Philipson, clinical director of the Kovler Comprehensive Diabetes Center, answers questions about the implications of this research.

For a complete copy of the research visit www.pnas.org.

1) Much of the focus in the U.S. is on type 2 diabetes, perhaps rightly so due to its larger incidence. Your paper published in PNAS spells out a potential path to detect and treat certain forms of rare type I diabetes. How exciting and promising is this research?

Although type 2 diabetes accounts for about 90% of the diabetes in the United States, close to 15-20 million people, the financial and emotional burden of type 1 diabetes is comparable because type 1 diabetes strikes primarily children. This makes the onset of complications in their young adulthood, potentially robbing them of good health in the prime of their life. The medical community invests a great deal of resources to treat these patients, We estimate that about 500,000 people, many who are undiagnosed, may have one of these rare forms of diabetes caused by single gene mutations, together termed monogenic diabetes. The recent attention on genes in type 2 diabetes, using genome wide scans, has identified several genes that are associated with type 2, but in most cases we don’t yet know why. In contrast, the single gene mutations that cause neonatal diabetes create a disease that is indistinguishable from type 1 diabetes. That is, the patients require insulin to survive and since the diabetes strikes within the first year of life, complications are also potentially earlier. Some of these forms are potentially treatable with pills, creating a transformational experience for the patient and family, with both greatly improved blood sugars and minimal hypoglycemia. The most recent discoveries are of mutations in the insulin gene itself that in most of the cases cause death of the beta cells, and again a disease indistinguishable from type 1 diabetes, but without autoimmunity, results. So far over forty patients with multiple different insulin gene mutations worldwide have been identified in only a little over three months since our discovery. This is a very exciting development, since it is a new model of human diabetes, with aspects that relate to ideas for treatment of both type 1 and type 2 diabetes.

2) Do you see much linkage from your ND research to this larger type 2 community?

Absolutely. The newly discovered insulin gene mutations are a kind of in between condition, where the beta cells are first impaired due to stress caused by the insulin gene mutations as the cell tries to make enough insulin. This results in the beta cells dying, but potential precursor cells should still exist, perhaps for many years. This means that we can examine the effects of potential treatments that might both rescue the beta cells and increase their number in these patients in the absence of the complications of continued stress from insulin resistance, as in type 2 diabetes, or of the autoimmune state, as in type 1 diabetes. There are also mouse and cell models where such potential treatments are being tested.

3) What would you tell parents of young children who read about your research and think their child might have this mutation or type I diabetes?

Patients and parents should discuss with their doctors whether they have had a key test – the anti-GAD65 antibody test. This is positive in about 85% of patients with type 1 diabetes, and really makes the diagnosis of type 1 diabetes. If it is negative, the disease might still be autoimmune, but if positive no further testing for genetic causes of diabetes is needed. Only a small fraction of patients with type 1 diabetes have had this test, it would seem by the inquiries I have had, yet it is recommended by every professional organization to make a diagnosis of type 1 diabetes. Other important features include exact age of onset, birthweight, family history of diabetes, personal history of autoimmune disorders, and other associated medical conditions. If there is still a possibility, there are several websites for further information, such as www.diabetesgenes.org and www.monogenicdiabetes.org. We are also setting up a United States registry of neonatal diabetes with support from the JDRF.

4) What is the next step in this ND research path?

The first is to identify more patients with these diseases. In the case of the potentially treatable KNCJ11 and ABCC8 mutations, we know of only about 30 patients in the United States. There are anywhere from a few hundred to a few thousand still to be discovered. Every single person that can improve their diabetes by switching to pills is a remarkable event for us. The second is to identify treatments for the mutations that do not yet have such treatments, and the third is to continue to identify other genetic causes of diabetes – there must be at least several more, based on the patients we and others have studied.

5) How important is it to communicate with the Diabetes Community about this research? How important is it for you to hear from parents and other patients from around the country?

Word is only slowly getting out about the importance of making a positive diagnosis of the kind of diabetes. This is especially so in very early onset or in families where multiple family members have diabetes. Rare conditions have the potential to be very informative for the causes and treatments of more common forms. We have identified patients in cities from Florida to Alaska, and with colleagues in Europe and Asia patients worldwide are getting identified and treated, if appropriate. It is a very exciting time.

Louis H. Philipson, MD, PhD, is Director of the Kovler Diabetes Center and Professor of Medicine in the Section of Endocrinology, Diabetes, and Metabolism at the University of Chicago. He also is Scientific Director at the Cellular and Tissue Based Processing cGMP Facility and the Director of the Islet Cell Biology Core Laboratory at the University of Chicago Diabetes Research and Training Center. To reach Dr. Philipson, email him at l-philipson@uchicago.edu.