Discovering Small Molecule Inducers of Alpha- to Beta-cell Transdifferentiation

Funding Type: 
Early Translational III
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

The goal of this project is to develop a new treatment for diabetes, based on increasing the number of insulin-producing cells in the pancreas, called beta-cells. In type I diabetes, the beta-cells are destroyed by the immune system, while in type II diabetes the beta-cells are more gradually lost due to the toxic effects of fat and glucose. Thus, in both major forms of diabetes, increasing the number of beta-cells would provide enormous benefit.
We have discovered recently that cells within the pancreas called alpha-cells that reside adjacent to the beta-cells can turn into beta-cells under certain conditions. Because the alpha-cells are not affected by either type I or type II diabetes, this finding opens the door to developing a therapy for diabetes based on stimulating the formation of new beta-cells from alpha cells. However, to achieve that goal, we would need to discover a drug that stimulates the alpha-cells to undergo such a conversion.
To that end, we will use high throughput screening, as done by pharmaceutical companies. For the screening, we will produce large numbers of alpha-like cells from human embryonic stem cells. Compounds that we discover will be tested in culture and then in animal models, with the goal of finding one that can be moved forward towards clinical testing in patients with diabetes. Such a therapy could be truly revolutionary in terms of its impact on the treatment of diabetes and on the lives of patients with diabetes.

Statement of Benefit to California: 

Diabetes, particularly type II, but also type I, is increasing in incidence and prevalence. As of 2005, California had approximately three million people with diabetes. About one third of the population of California has prediabetes, suggesting that the incidence will continue to increase. Diabetes is particularly prevalent in regions of the state such as the Central Valley, which has a large Hispanic population, which is particularly prone to type II diabetes. In 2005, the cost of treating diabetes in California was estimated to be approximately 24.5 billion dollars. In addition to diabetes itself, diabetes is a major contributor to cardiovascular disease risk, and more recently has been recognized as a significant risk factor for a number of types of cancer. Thus, a novel therapy for diabetes such as that proposed here to generate new insulin-producing beta-cells would have an enormous impact on the health of the citizens of California, resulting in increased quality of life and decreased health care costs.