Grant: Project Grant

There is an inverse relationship between the functionality of a cell and its ability to proliferate, but the underlying mechanisms are still not clear. Our group has recently demonstrated that normal levels of insulin production in pancreatic beta-cells constrain beta-cell proliferation. This is interesting, because both type 1 and type 2 diabetes may be associated with early periods of insulin over-production, which could theoretically have a negative effect on beta-cell adaptation to stress. The overall goal of the proposed research is to further test this hypothesis in the context of type 1 and type 2 diabetes models, and to determine the molecular mechanisms that link insulin production to beta-cell fate decisions. To test our hypothesis, we have generated mouse models where insulin production can be rapidly turned off at the level of the insulin gene in adult animals, as well as complementary cell culture models. We have already conducted a survey of all the genes expressed in beta-cells to uncover the mechanisms that underlie these cell fate changes, and the proposed research will be focused on determining the molecular mechanisms involved in beta-cell proliferation after the suppression of insulin production. We expect that the results of our study will reveal new processes that control whether the beta-cells divide. This new information will be foundational in efforts to regenerate beta-cells for the treatment of type 1 diabetes and type 2 diabetes. If we are able to uncover processes that can be harnessed to produce more beta-cells or better beta-cells, then it would open up new therapeutic options.