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Molecular mechanisms of the regulation of the function of pancreatic B cells


We first demonstrated, that pancreatic B cells expresses NAD(P)H oxidase and this enzyme seems to be involved with superoxide generation during the process of insulin secretion. This study started after our observation that glucose controls antioxidant enzyme activities such as superoxide dismutase (SOD), catalyze and glutathione peroxidase. We found that the increase in SOD activity is directly correlated with the augment in glucose concentration. Considering that SOD activity increases concomitantly with raises in superoxide generation in several tissues, we examined the same phenomenon in pancreatic B. a direct correlation between the increase of glucose concentration and superoxide generation by isolated rat islets and that the production of these compounds was dependent on NAD(P)H oxidase were found. Unpublished data from out laboratory have shown that glucose, palmitate and interleukin-1B increase superoxide generation through NAD(P)H oxidase activity. These compounds also increase the expression of some NAD(P)H oxidase components. The function NAD(P)H oxidase in the process of insulin secretion and the action of other endogen substances on this enzyme activity were then investigated. Isolated pancreatic islets chronically exposed to high glucose concentration, free faty acids, or interleukins have show impaired insulin secretion. These changes are, at least in part, due to the production of reactive oxygen species. We also investigated if NAD(P)H oxidase is also involved in these process. This project will initially study the participation of NAD(P)H oxidase in the molecular mechanisms that regulates the glucose - and palmitate-induced insulin secretion. This study and the evaluation of the effect of oxidative stress in RINm5F, will be the first step to clarify the participation of this enzyme in the impairment of secretory events in pancreatic B cells. (AU)

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