We propose to study the long term modulating effects of pregnancy on pancreatic islets of Langerhans. Although rapid regulation of insulin secretion by nutrients and hormones has been the focus of considerable research, the examination of long-term modulation of islets has received much less attention. Pregnancy is a normally occurring physiological condition where there is a long term need for increased insulin secretion at normal serum glucose levels. This demand is met by many major alterations in islet structure and function. Among these changes the most important are: (a) an increase in glucose-stimulated insulin secretion (4-10 fold at normal serum glucose concentrations); (b) a lowering of the glucose-stimulation threshold; and (c) increased beta- cell proliferation. Using species specific lactogenic hormones (placental lactogen and prolactin which share a common receptor) we have demonstrated that these hormones induce all of the known changes in islets that occur during pregnancy. Using islets from pregnancy and islets treated with lactogenic hormones in vitro we will determine: (1) The signal transduction pathways used by prolactin receptors in islets. (2) How the lactogen induced changes in gene expression lead to enhanced insulin secretion. (3) How the lactogen induced changes in metabolism lead to enhanced insulin secretion. (4) How lactogens stimulate B-cell proliferation. (5) The role of lactogens in the development and growth of islets. (6) The glucose dependence of the lactogen induced changes in vivo and how these changes compare with those induced by in vivo glucose infusion. Although mechanisms of lactogen regulation of islets will likely share some features with other prolactin sensitive cells, they will also be very unique as they must include features for affecting the islet specific metabolic sensing system. Our long term goal is to delineate the mechanisms responsible for the increased islet function observed during pregnancy. These studies will provide important information on the long term regulation of islet function and beta-cell mass. Understanding the regulation of beta-cell glucose sensitivity has important implications for understanding the progression of events that lead to gestational and type II diabetes. In addition, the studies on regulation of islet beta- cell growth will provide essential information on development of beta- cells and the growth potential of differentiated islet beta-cells.
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