Insulin is synthesized in the b cells of the islets of Langerhans. Physiological glucose levels are maintained through the action of this hormone on peripheral tissues, with defects in P cell function involved in initiating and maintaining hyperglycemia in diabetics. Little detailed information was known about the factors controlling pancreas development and islet P cell function until recently. However, our understanding has increased greatly as a result of studies on the insulin promoter, which led to the identification and molecular characterization of the islet-enriched transcription factors PAX6, PDX-1, MafA and BETA2. The gene knockouts performed on these factors and other pancreas-enriched factors are helping elucidate the events influencing pancreatic morphogenesis. The next step is to understand how the expression and activity levels of these important regulators are controlled. It is likely that new factors necessary for P cell function will be revealed in these studies. Because of their unique expression pattern and fundamental significance to P cells, our objectives are focused on defining the transcription factors involved in controlling selective .expression of pdx-1 and ma/A. In addition, we will test the in vivo significance to the P cell of the p300 and CBP co-activators, adapter molecules that appear critical for expression of many genes associated with b-cell identity. These studies will provide greater insight into the transcriptional components fundamental to P cell activity, and likely provide information that will be essential in generating acceptable islet-like cells for therapeutic treatment of type 1 and type 2 diabetics.
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