Type I insulin dependent diabetes mellitus (IDDM) is a familial disorder with primarily juvenile onset that is characterized by the autoimmune destruction of beta islet cells in the pancreas, resulting in insufficient insulin secretion and hyperglycemia. Type II or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes, with both genetic and environmental (particularly obesity) factors contributing to its development. The inability of pancreatic beta cells to compensate for increased insulin demand, such as by increased proliferation, in obese individuals appears to contribute to NIDDM. The E2F transcription factor family plays critical roles in the regulation of cell cycle progression. Our recent studies of mice deficient for the E2F1 and E2F2 transcription factors have revealed essential roles for these proteins in the regulation of pancreatic beta cell maintenance. Mice deficient for both E2F 1 and E2F2 develop non-autoimmune insulin dependent diabetes with high penetrance. Surprisingly, the requirement for E2F 1 and E2F2 in preventing beta islet cell loss does not appear to be autonomous to islet cells, but instead appears to reside in bone marrow cells, as transplantation ofwildtype bone marrow can prevent or rescue diabetes in E2F1-/-E2F2-/- mice. We propose to characterize the nature of this non-islet autonomous control of beta islet cell maintenance. Understanding how beta islet cell maintenance is influenced by bone marrow derived cells should provide important insight into the design of therapies to boost islet mass and function in patients with either Type I or II diabetes. We propose three specific aims, although the first two aims should represent the bulk of our efforts. The third aim will require a more defined description of the bone marrow derived cell type(s) that mediates islet maintenance, such that at this point the exact mouse mutants to be analyzed is speculative. 1) Prevention of beta islet degeneration in E2F1-/-E2F2-/- mice by transplantation of defined hematopoietic subsets. 2) Further characterization of non-cell autonomous control of beta islet maintenance using islet transplantation. 3) Analysis of beta islet mass and function in mutant mice with defined hematopoietic defects.

R21DK063299

2003-06-04

2005-05-31