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High-glucose level exerts deleterious effects on pancreatic β cells,but the mechanisms remain unclear.Calcium/calmodulin-dependent serine protein kinase (CASK) plays a vital role in neural development and release of neurotransmitters,and probably plays a role in the anchoring of insulin on pancreatic β cell membrane.Hypoxia-inducible factor 1a (HIF1α) is involved in β-cell dysfunction.The aim of this study was to provide some basic evidence that CASK could be involved in glucotoxicity-induced insulin secretion dysfunction mediated by HIF1α in INS-1E cells.CASK overexpression plasmid,HIF1α agonist (CoCl2),and HIF1α selective inhibitor (KC7F2) were used.The results showed that chronic stimulation with high glucose could induce insulin secretion dysfunction in INS-1E β cells.Overexpression of CASK partially reversed the effects of high glucose on insulin secretion.CoCl2 reduced the expression of CASK,but KC7F2 reversed the glucotoxicityinduced CASK level reduction.These results suggested that glucotoxicity-induced insulin secretion defects in INS-1E cells could be mediated by HIF1α via the down-regulation of CASK.