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标题：Hexosamine pathway but not interstitial changes mediates glucotoxicity in pancreatic β-cells as assessed by cytosolic Ca²⁺ response to glucose
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作者：Kazuhiro Yanagida ; Yuko Maejima ; Putra Santoso 等
期刊名称：Aging
出版年度：2014
卷号：6
期号：3
页码：207-214
出版社：U.S.Department of Health & Human Service
摘要：Hyperglycemia impairs insulin secretion as well as insulin action, being recognized as the glucotoxicity that accelerates diabetes. However, the mechanism underlying the glucotoxicity in pancreatic β-cells is not thoroughly understood. Hyperglycemia alters glucose metabolism within β-cells and interstitial conditions around β-cells, including elevated osmolarity and increased concentrations of insulin and ATP released from overstimulated β-cells. In this study, to explore direct effects of these alterations on β-cells, single β-cells isolated from rat islets were cultured for 3 days with high (22.3 mM) glucose (HG), compared with control 5.6 mM glucose, followed by their functional assessment by measuring cytosolic Ca²⁺ concentration ([Ca²⁺]_i). The [Ca²⁺]_iresponse to a physiological rise in glucose concentration to 8.3 mM was impaired in b-cells following culture with HG for 3 days, while it was preserved in β-cells following culture with non-metabolizable L-glucose and with elevated osmolarity, insulin and ATP. This HG-induced impairment of [Ca²⁺]_iresponse to 8.3 mM glucose was prevented by adding azaserine, a hexosamine pathway inhibitor, into HG culture. Conversely, culture with glucosamine, which increases the hexosamine pathway flux, impaired [Ca²⁺]_iresponse to 8.3 mM glucose, mimicking HG. These results suggest that the HG-associated abnormal glucose metabolism through hexosamine pathway, but not elevated osmolarity, insulin and ATP, plays a major role in the glucotoxicity to impair the secretory function of pancreatic β-cells.
关键词：Glucotoxicity; hexosamine pathway; insulin secretion