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Glibenclamide-induced Insulin Secretion is Partly Mediated by Aquaporin-7 and Aquaporin-1 in Pancreatic β -cell

【摘要】:正Objectives Glibenclamide is a potent second - generation sulfonylurea drug to promote insulin secretion for the treatment of type 2 diabetes mellitus;inhibition of the ATP - sensitive potassium(K_(ATP) ) channels is its main molecular mechanism.Recent studies have reported that Aquaporin 7(AQP7 ),a channel protein permeable to water,glycerol and urea,is expressed in pancreatic β - cells and involved in the regulation of insulin secretion.Aquaporin 1(AQP1),known as an osmotic water channel,is also involved in regulation of the functions of some exocrine and endocrine glands.Several known inhibitor of aquaporins such as acetazolamide,furosemide and bumetanide,their chemical structure are similar to glibenclamide,all have a sulfonamide structure.These data suggest that glibenclamide may affect the function or expression of AQPs. The purpose of this study therefore is to determine whether glibenclamide can regulate the water channel proteins in pancreatic β - cells,thereby promoting insulin secretion.Methods The expression of AQP1 and AQP7 in MIN6 cells were detected using RT - PCR and Western blot methods.The roles of AQP1 and AQP7 on insulin secretion in the MIN6 cells were evaluated after transected with siRNA of AQP7 and AQP1.The intracellular co - localization of AQP1,AQP7 and K_(ATP) channel were detected by confocal immunoflorescent microscopy. Interactions of AQP1 or AQP7 with K_(ATP) channel were measured by co - immunoprecipitation,respectively. The effects of glibenclamide on phosphorylation of AQP1 and AQP7 were assessed in MIN6 cells by immunoprecipitation and Western blot methods.An effect of glibenclamide on intracellular translocation of AQP7 was examined in MIN6 cells by confocal microscopy.We also observed the effects of glibenclamide on K_(ATP) channel expression in MIN6 cells.Results In this study,both AQP1 and AQP7 were found to be expressed in MIN6 cells.Knockdown of AQP1 or AQP7 in MIN6 cells clearly impaired insulin secretion stimula- ted by glucose,KCl or glibenclamide,respectively.Glibenclamid could up - regulate the expression of AQP7 in MIN6 cells and mouse pancreas,but down - regulate the expression of AQP1.In MIN6 cells,the glibenclamide could weaken the interaction between AQP7 and K_(ATP) channel,enhanced the interaction of AQP1 with K_(ATP) channel;increased the phosphorylation of AQP1 and AQP7,and promoted the translocation of AQP7 and K_(ATP) channel to the cell membrane.Conclusions Here,we report the novel observation that both AQP1 and AQP7 are expressed in MIN6 cells,and participate the regulation of insulin secretion.Regulation of AQPs might be a new mechanism of glibenclamide to promote insulin secretion.

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