The single most important pathological finding in insulin-dependent diabetes mellitus (IDDM) is a substantial decrease in the absolute number of insuling-secreting pancreatic beta cells. Additionally, impaired beta cell function is a frequent finding in non-insulin-dependent diabetes (NIDDM). Compelling experimental and epidemiological evidence indicates that, at least in some forms of IDDM, environmental factors play an important role in the critical depletion of insular tissue. Functional alterations in beta cells after experimental exposure to chemicals have also been demonstrated. N-nitroso compounds, their precursors and other structurally similar chemicals are ubiquitous environmental pollutants that are commonly present in human food. Several of these chemicals have been found to specifically intoxicate pancreatic beta cells. The mechanisms by which these toxins can selectively interact with beta cells resulting in functional alterations and cell-death remain to be fully elucidated. Because of the complexities of chemical metabolism and the difficulties of determining mechanisms of cytotoxicity in intact animals, mechanistic studies are uniquely suited for tissue culture systems. In this investigation, cultured pancreatic islet and insulinoma cells from the rat will be exposed to various beta cell toxins and used to: 1) characterize the types of lesions produced in beta cell DNA by these toxins; 2) study the repair of toxin-induced DNA lesions; 3) investigate the role of the poly (ADP-ribose) system in chemically-induced beta cell damage; 4) assess the role of oxygen free radicals in chemically-induced beta cell damage; and 5) determine alterations in pyridine nucleotide cycles after exposure to beta cell toxins. These studies will employ innovative new technologies, such as computerized microspectrofluorometry for the localization and quantitation of specific changes within beta cells, and high pressure liquid chromatography for assessment of alterations in DNA, to help determine the mechanisms by which certain chemicals intoxicate beta cells. When executed, these studies will provide a more complete understanding of how enviromental pollutants can selectively interact with normal beta cells to cause functional impairment and/or the death of these cells, thereby precipitating diabetes mellitus.
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