Amylin is a product of the normal beta cell in the endocrine pancreas. Its existence was unknown until it was found in amyloid deposits in patients with noninsulin-dependent diabetes mellitus in 1987. We have cloned the cDNA for the amylin precursor and found that amylin is expressed only in the pancreatic islet and is encoded in a 93 amino acid precursor that is presumed to undergo proteolytic processing in the beta cell. The processed, mature amylin is packaged in secretory granules together with insulin and is probably secreted along with insulin. At present, the factors that regulate the expression and secretion of amylin are unknown, as are the cellular targets of amylin action. In this proposal we will direct our efforts to defining the normal functional role of amylin so as to understand how it contributes to the pathogenesis of diabetes. Molecular probes to detect amylin mRNA and protein species will be utilized to measure expression in islets and cultured insulinoma cells. Amylin secretion in response to secretogogues will be studied with sensitive immunoassays. These studies should define the conditions under which amylin is secreted and how this secretion relates to insulin secretion. The site(s) of action of amylin will be defined by identifying high affinity, specific receptors in appropriate tissues. These receptors will be purified and cloned to begin to define the function of this hormone. This information could be important in our understanding of the normal physiology of amylin, as well as type I diabetes where amylin is presumably absent. To understand the role of amylin in noninsulin-dependent diabetes, animal models of these disorders will be studied to define if amylin is expressed inappropriately early in the course of this disease and, if so, how this could contribute to the development of NIDDM. Abnormalities in the pattern of secretion, as well as the deposition of islet amyloid, will be tested. A possible link of amylin with the genetics of NIDDM will be tested using DNA polymorphisms and linkage studies in families with NIDDM. These studies should shed light on the importance and application of amylin in understanding normal and abnormal beta cell function.
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