Innovative Research and Type 1 Diabetes: “Of Mice and Men”

In a recent blog, I told you my vision for a potential treatment of type 1 diabetes mellitus. I proposed that a combination of several modes of therapy might enable the beta cells in the islets of Langerhans to produce insulin. Clearly the goal of any form of diabetes treatment is to preserve remaining pancreatic islets by preventing future destruction and to potentially regenerate new islet cells that were destroyed. The Protége Trial spearheaded by Dr. Kevan Herold uses monoclonal antibodies to prevent destruction of the islet cells by killer T cells and thus prolong the "honeymoon" period indefinitely in humans. Dr. Melton's study (Nature, 2008) genetically reprogrammed existing mouse pancreatic exocrine (digestive cells) into endocrine (islet cells) by introducing three specific genes using a friendly virus to infect the cells. Over the next 10 days, the specific genes transformed the digestive pancreatic cells into islet cells that were able to produce insulin.

In the October 30, 2008, issue of The New England Journal of Medicine, Ludvigsson et. al., reported the administration of GAD-alum (an autoantigen in type 1 diabetes) in an attempt to induce immunologic tolerance (a vaccine). The study was conducted based on information obtained in a breed of mouse destined to become diabetic but not yet hyperglycemic. When GAD was administered to these pre-diabetic mice the onset of type 1 diabetes was delayed. In this study, the GAD-alum was injected into young patients (10-18 years) with recent onset type 1 diabetes to determine if treatment with the autoantigen would reduce or stop the loss of residual insulin secretion. Unfortunately, despite the fact that treatment with GAD-alum had an effect on slowing the loss of residual beta-cell function up to 30 months after intervention, it did not change the insulin requirement. In addition, GAD-alum therapy initiated six months or more after diagnosis did not show a protective effect on disease progression. Dr. Denise Faustman, in a companion article of the same NEJM issue, "Immunotherapy on Trial for New-Onset Type 1 Diabetes," speculated that if the GAD-alum is injected into pre-diabetic children and adolescents, might it prevent the onset of type 1 diabetes more effectively than in children and adolescents already diagnosed with new onset disease? Clearly, this will open up an entire new portal for original research in humans.

In November 2008 a new study conducted by Dr. Louvet et al. from the University of California at San Francisco was published in the Proceedings of the National Academy of Sciences. The study "Tyrosine kinase inhibitors reverse type 1 diabetes in non-obese diabetic mice" demonstrated that this new class of drugs used in the treatment of certain cancers (Chronic Myelogenous Leukemia and others) can prevent or reverse new onset diabetes in mice. Treatment of pre-diabetic and new onset diabetic mice with imatinib (Gleevec) prevented and reversed type 1 diabetes. Similar results were noted in the use sunitinib (Sutent). The use of imatinib led to a prolonged remission (80 percent of mice) after discontinuation of therapy (10 weeks). Therefore, the remission did not require continuous treatment. In addition, and of extreme importance, the safety profile of imatinib and sunitinib is known to be acceptable in humans.