IRS-2 Function in Beta Cell Physiology

This proposal focuses on the role of IRS-2 in b-cell function. Immunoflourescence experiments are used to explore the role of IRS-2 in the proliferation and survival of putative islet precursor cells.  Islet clusters isolated from mice lacking IRS-2 or IRS-1 are studied in vitro to establish the role of IRS-2 in proliferation/differentiation, apoptosis and insulin secretion.  An irs-2 transgene is expressed in b-cells of IRS2-deficient mice to test the hypothesis that expression of IRS-2 exclusively in b-cells is sufficient to suppress diabetes in the IRS2-/- mouse; if IRS-2 is islet autologous then the IRS-2 transgene is expected to prevent the onset of diabetes in the IRS2-/- mouse.  Finally, we propose to disrupt IRS-2 exclusively in b-cells or hepatocytes to determine which cell type is most important for the development of diabetes in this system.