We propose to study the long term modulating effects of lactogenic activity on islets. Although rapid regulation of insulin secretion by nutrients and hormones has been the focus of much research, the examination of long-term modulation (ie. up and down regulation) of insulin secretion has not received similar attention. Pregnancy is a condition during which the islets undergo long term modulation, resulting in major changes in structure and function to accommodate the increased demand for insulin. These changes include: 1) A decreased threshold for glucose stimulated insulin secretion; 2) Enhanced above threshold insulin secretion (4-10 fold at physiologic glucose concentrations); 3) Increased communication among B- cells via gap junctions; and 4) Increased B-cell growth. Since prolactin induces the same alterations in islet function, we have proposed that it is lactogenic activity which induces these changes during pregnancy. Using cultured rat islets treated with lactogen (homologous prolactin or placental lactogen) as a model for studying the long term up-regulation of islets, we propose to: 1) Determine the role of placental lactogens in up- regulating the islet during pregnancy in rodents; 2) Determine the mechanisms responsible for the phasic changes seen in islet B-cell growth and insulin secretion during pregnancy; 3) Determine the lactogen induced changes in islet metabolism and B-cell coupling which lead to enhanced insulin secretion; 4) Determine the alterations in B-cell heterogeneity which lead to adaptation of the islet to pregnancy; 5) Determine the effect of lactogens in regulating islet B-cell growth and proto-oncogene expression; and 6) Determine the effect of human placental lactogen on B- cell growth in human islets in vitro. This in vitro model of islets provides a unique opportunity to study major alterations of B-cell structure and function in response to long-term modulation. Studies based on this model will not only provide important information about mechanisms of B-cell responses to lactogenic hormones, but will also aid in determining the function of B-cell junctional coupling, the relevant changes in B-cell metabolism which regulate insulin secretion, and the regulation of B-cell growth. These investigations will provide insight into how the islet adapts during pregnancy. Modulation of islet glucose sensitivity is important in pregnancy as well as in type II diabetes. Aside from our investigations there are surprisingly few studies that focus on the long-term regulation of B-cell glucose sensitivity. Our studies on the modulation of B-cell glucose sensitivity in the normal islet have important implications in understanding aspects of gestational and type II diabetes. In addition, our investigations on the regulation of islet B-cell growth will provide important on the growth potential of differentiated islet B-cells.
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