The proposed Disease Team is directed at developing new therapies for diabetes. There are two major forms of diabetes. The first is a disorder of the immune system in which immune cells kill the insulin producing cells in the pancreas, known as beta-cells. The lack of insulin makes is impossible for glucose to enter cells, leading the high levels of glucose in the blood that are characteristic of diabetes. This disorder usually begins in childhood. The second major form of diabetes is strongly associated with obesity. In this complex disorder, resistance to the effects of insulin leads to high levels of blood glucose. In addition, over time the beta-cells become dysfunctional and eventually die. Frank diabetes does not occur until there are too few beta-cells to secrete enough insulin to control the blood glucose. Thus, in both major forms of diabetes, beta-cell dysfunction and/or death is central to the disease process. The Diabetes Team that we are planning will pursue a number of approaches to increasing the number of beta-cells in people with diabetes. In one approach, we will use embryonic stem cells, developed with conventional and novel methods, to create beta-cells outside the body. Those cells will be transplanted, first into animal models of diabetes and then in small scale human trials. The goal will be to determine the most efficient and safest method of inducing embryonic stem cells to become beta-cells. In addition to embryonic stem cells, Disease Team members will work on inducing adult pancreatic cells to differentiate into beta-cells. These adult progenitor cells have been controversial, with some investigators even questioning their existence. However, more recent evidence indicates that there are beta-cell progenitors in the adult pancreas, but they remain quiescent for the most part. However, if we can understand more about how to induce those cells to become beta-cells, it may be possible to repopulate the pancreas of diabetics who have lost the beta-cells. Under most circumstances, beta-cells regenerate themselves by splitting into two, a process called replication. However, beta-cell replication occurs infrequently and we do not understand the factors that are required to signal to the beta-cell that it must replicate itself. Developing a sufficiently detailed understanding of those factors to allow us to stimulate beta-cell replication in patients with diabetes will be another area of focus for the proposed Disease Team. Finally, an important element of the team will be to test therapies that are developed in animal models and eventually in small-scale human clinical trials. We believe that combination of approaches that are planned by the members of the proposed Diabetes Disease Team will lead to new treatments for diabetes.
Diabetes, particularly type II diabetes, is rapidly increasing in prevalence in the United States, including California. This is due primarily to the rapid increase in the percentage of the population who are obese. It is clear that frank type II diabetes does not occur until beta-cells have been damaged to the point where they are unable to compensate for the increase demands placed upon them by peripheral insulin resistance. In the other major form of diabetes, autoimmune or Type I, beta-cells are destroyed by an aberrant immune response. Thus, in both major forms of diabetes afflicting citizens of California, beta-cells play a critical role in the development of diabetes. The focus of this proposal is on preventing or treating diabetes by increasing the number of beta-cells. Through interactions with biotechnology companies, the commercialization of new therapies for diabetes should benefit the economy of California. More directly, new therapies will benefit the citizens of California by improving the state of health of those citizens afflicted by diabetes.