Regulation of pancreatic β-cell function by glutathione

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Reactive oxygen species (ROS) is a factor for tissue injury and participates in intracellular signal pathways. Glutathione (GSH) plays a central role in scavenging ROS to retain persistent and stable physiological functions in cells. GSH also regulates intracellular signal pathways through redox regulation. This study was addressed to clarify a role of GSH in the regulation of beta-cell function. The results obtained in this year are :(1) One of the striking characteristics of pancreatic β-cells is that the cells possess low concentration of GSH.Gamma-Glutamylcysteine synthetase (γ-GCS) is a key enzyme for the GSH synthesis. In order to see the effect of further lowing the levels of GSH on the pancreatic β-cell, we constructed hammerhead ribozymes coupled with antisense nucleotides for γ-GCS heavy subunit (catalytic) and light stubunit (regulatory), respectively, and transfected to rat β-cells, MIN-6. We next studied on the effect of decrease of GSH synthesis on the β-cell function.a) … More The transfection of either of the ribozymes caused of a decrease of the GSH synthesis followed by a decrease of the GSH concentration to 40% of the control levels.b) Persistent suppression of the GSH synthesis led an enhancement of insulin secretion from β-cells.c) The suppression of GSH synthesis also enhanced the intracellular concentration of calcium, which might be a factor of the increase of insulin secretion.d) MIN-6 cells transfected with proinsulin reporter sene showed that the promoter activity was stimulated in the cells with anti-γ-GCS ribozymes.(2) Response against oxidative stress was studied using MIN-6 cells incubated in high-glucose (27 mM) or normal-glucose (5.5 mM). Exposure of MIN-6 cells with high-glucose to hydrogen peroxide caused an impairment of anti-apoptotic signals mediated by P13-kinase/Akt. Treatment of these cells with GSH ester restored the cell damage induced by hydrogen peroxide, suggesting an important role of GSH in defense mechanism and intracellular signals in pancreatic β-cell. Less