Beta Cell Regeneration: The Latest Update from the University of Pittsburgh
In recent blogs, I offered 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. The goal of any form of diabetes treatment is to preserve remaining pancreatic islets by preventing future destruction and potentially regenerate new islet cells that were destroyed. The Protége Trial spearheaded by Kevan Herold, MD, 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. During the next 10 days, the specific genes transformed the digestive pancreatic cells into islet cells that were able to produce insulin.
In early January 2009, Andrew Stewart, MD, and colleagues published a significant research paper called "Survey of the Human Pancreatic Beta Cell G1/S Proteome Reveals a Potential Therapeutic Role for Cdk-6 and Cyclin D1 in Enhancing Human Beta Cell Replication and Function in Vivo" in the journal Diabetes associated with the American Diabetes Association. (I shall translate, don't worry). As has been known for many years, due to an autoimmune process in the pathogenesis of Type 1 Diabetes, pancreatic Beta islet cells that produce insulin are destroyed. Type 2 diabetes results because of the body's inability to properly utilize its own insulin, as well as destruction of beta cells as the disease progresses. Even more interestingly, despite the relentless destruction of beta cells, the pancreas continues to regenerate new pancreatic islet cells in both type 1 and type 2 diabetes. Thus, as I have indicated in previous blogs, treatment of diabetes will need to encompass prolongation of current beta cell life along with replacing the destroyed cells with new nascent insulin producing cells.
Dr. Stewart inventoried the proteins that control a specific cell cycle check-point in the human islet cell and compared them to those in mice islet cells to determine if these proteins might enhance human beta cell replication. Two of the most promising proteins out of 30 potential candidates were cdk-6 and cyclin D1. Via gene therapy, the two proteins were injected into human beta cells and then transplanted into diabetic NOD mice. The expression of cdk-6 and cyclin D1 stimulated human beta cell replication (production of new functional beta islet cells that produce insulin) faster than normal regeneration and succeeded in maintaining glucose control for the entire six weeks of the study. In summary, the authors noted that using this model, human beta cell replication can be stimulated and studied in vivo (in living animals such as mice).
Why is this important? The key is to have a ready supply of healthy pancreatic islet cells (Beta) that produce insulin available. In the very recent past, via the development of recombinant DNA techniques, endless supplies of human insulin could be made available. Enter the possibility with future research the availability of "unlimited" supplies of human pancreatic beta cells without worrying about stem cell research. At this time, most successful transplantation involves the transplant of cadaveric whole pancreases (often in conjunction with a kidney) or islet cell transplants.. The transplantation of islet cells via the portal vein (Edmonton Protocol) has been less promising because many centers have been unable to replicate Dr. Shapiro's success. In addition, multiple islet cell transplants were required that did NOT eliminate the need for exogenous insulin. This current study holds promise that human islet cells can be stimulated to replicate successfully (and quickly) in a mouse.
Dr. Stewart cautioned, however, that a cure for diabetes will not be ready in the immediate future. Nevertheless, if researchers can find a way to develop a ready supply of new functioning islet cells that can produce insulin and transplant them successfully into patients with diabetes, one side of the equation will be solved!
I will keep you posted.