The role of NAD(P)H oxidase in the molecular mechanisms of pancreatic beta cell physiology

Abstract

We have previously shown that pancreatic beta cells express the superoxide-producing enzyme NAD(P)H oxidase and that the decrease in its activity importantly impairs glucose metabolism, intracellular calcium oscillations and glucose-stimulated insulin secretion (GSIS). Chronic exposure to fatty acids or interleukins induce changes in the insulin secretion mechanisms that are partially due to modulation of NAD(P)H oxidase activity. Angiotensin II (Ang II) via AT1 receptor activates NAD(p)H oxidase in isolated pancreatic islets thus modulating insulin secretion. Preliminary data from our laboratory show that hydrogen peroxide (H202) production is dramatically reduced after NAD(p)H oxidase inhibition. We also have strong evidence suggesting that pentose-phosphate pathway activation in GSIS has a pivotal role in the maintenance of the redox environment of pancreatic beta cells. There is also evidence that NADPH oxidase participates in the development of insulin resistance in aging, what can be partially reversed by dehydropiandrosterone (DHEA) treatment. Thus, we intend to focus our studies in the role of NAD(P)H oxidase and H202 in the cellular mechanisms which couple glucose metabolism to insulin and glucagon secretion and the participation of Ang II, DHEA, melatonin and ethanol in the regulation of the activity of this enzyme. BRIN BD11 and INS1E cells, which possess physiological characteristics similar to rat beta cells will be also used. (AU)