Diabetes mellitus is a metabolic disorder that currently affects over 180 million people worldwide. Common to all forms of diabetes is the gradual loss of functional insulin-producing p-cells in the endocrine pancreas. A hierarchy of transcription factors has been demonstrated to control the development and function of the endocrine pancreas. Islet-1 (lsl-1), is a homeo-domain containing transcription factor that is expressed in embryonic foregut and later in adult islet cells. Furthermore, lsl-1 mutations have been identified in type 2 diabetics suggesting that lsl-1 may also play a major role in the etiology of diabetes. While previous studies using isl-1 knockout mice have revealed a vital role for lsl-1 in first wave of endocrine cell differentiation, its role in the second wave of endocrine cell development, in regulation of p-cell function and growth, as well as in adult p-cell expansion have not been addressed due to the early embryonic lethality of lsl-1 deficient mice. We have begun to assess lsl-1 function in second wave of endocrine cell development, p-cell metabolism and p-cell expansion through conditional gene targeting using the Cre/LoxP recombination system. In preliminary work required for this application we have generated and tested all LoxP and Cre mice necessary for the proposed experiments. The specific aims of this proposal are: First, we will determine the role of lsl-1 during second wave of endocrine cell development by using an endoderm-specific ablation of Isl- 1 mouse line. Second, we will investigate the contribution of lsl-1 to p-cell survival and glucose stimulated insulin secretion using a p-cell-specific deletion of lsl-1 mouse line. Third, we will investigate the role of lsl-1 during adult p-cell expansion in to increased metabolic demands of pregnancy, high fat diet feeding and partial pancreatectomy using an inducible Cre-recombinase system. Together these studies will further our understanding of the transcriptional networks controlling the second wave of endocrine cell differentiation, p-cell metabolism, p-cell expansion and the pathogenesis of diabetes. Insights gained from the role of lsl-1 will be used for designing innovative biologically based therapy with the goal to provide novel treatments for diabetes.