MECHANISM OF ISLET GROWTH AND DIFFERENTIATION

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Diabetes mellitus, whether IDDM or NIDDM, can be considered the result of inadequate mass of functional pancreatic beta cells, in the former due to a selective autoimmune destruction of these cells and in the latter to an inability to compensate for the extra demand of obesity or insulin resistance. Thus once immune destruction can be arrested,both types of diabetes could be treated if we knew how to stimulate the expansion of the beta-cells in vivo or in vitro. In all tissues studied the regulation of growth requires a complex orchestration of numerous stimuli and growth factors. The partial pancreatectomy rat model is a well defined model of beta- cell and pancreatic cell growth-that offers the opportunity to study the regulation of this process in the pancreas. In this model-the regeneration of pancreas occurs by two pathways: replication of pre- existing pancreatic beta-cells and by expansion of the duct epithelium and its subsequent differentiation into endocrine and exocrine tissue. Data from this model and from transgenic mice that over-express TGF- alpha: provide the first strong evidence of precursor cells in the adult pancreatic ducts. Both in vivo and in vitro experiments are proposed to characterize these putative precursor cells and to explore whether there are separate populations for exocrine and endocrine cells. During this regeneration several growth factors (TGF-beta, IGF-I, hepatocyte growth factor) show significant changes in their expression as measured by RNA analysis and immunochemistry; these changes suggest the involvement of these factors in the process. The role of each of these factors as well as TGF-alpha and gastrin will be tested on cultured duct epithelium and on cultured islet monolayers to determine its effect on proliferation, morphogenesis and differentiation of these cells. In addition the requirements for epithelial-mesenchymal interactions and for 3 dimensional organization of the ductal cells for each of these effects will be assessed. With the data from these experiments scenarios for interactions of factors can be tested using similar protocols in an effort to reconstruct in vitro the defined and structured sequence of events that occur in vivo. These experiments should provide a better understanding of the regulation of pancreatic growth and differentiation. Knowledge of how to stimulate growth and differentiation of islet cells may lead to new therapies.