α-cell glucokinase suppresses glucose-regulated glucagon secretion.
α-cell glucokinase suppresses glucose-regulated glucagon secretion.
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DOI：
10.1038/s41467-018-03034-0
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发表时间：
2018-02-07
影响因子：
16.6
通讯作者：
Thorens B
中科院分区：
文献类型：
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作者：
Basco D;Zhang Q;Salehi A;Tarasov A;Dolci W;Herrera P;Spiliotis I;Berney X;Tarussio D;Rorsman P;Thorens B
胰腺α细胞的胰高血糖素分泌由低血糖触发并由高葡萄糖水平抑制;胰高血糖素分泌抑制受损是1型和2型糖尿病的标志。在这里，我们发现α-细胞葡萄糖激酶（Gck）在胰高血糖素分泌的控制中发挥作用。利用Gck α细胞特异性失活的小鼠（αGckKO小鼠），我们发现葡萄糖激酶是葡萄糖依赖性增加细胞内ATP/ADP比值和关闭α细胞中KATP通道以及在正常血糖和高血糖水平下抑制胰高血糖素分泌所必需的。αGckKO小鼠在进食状态下表现出高胰高血糖素血症，这与肝促胰高血糖素基因表达和肝葡萄糖输出能力增加有关。在成年小鼠中，进食后高胰高血糖素血症进一步增加，并发生葡萄糖耐受不良。因此，葡萄糖激酶控制α-细胞代谢途径，抑制血糖正常或高于血糖正常水平的分泌;胰高血糖素分泌的异常抑制使肝脏葡萄糖代谢失调，并随着时间的推移诱导糖尿病前期表型。胰高血糖素分泌在低血糖症期间被促进，并被葡萄糖水平升高抑制。在此，巴斯科等人表明，葡萄糖激酶通过调节细胞内ATP/ADP比率和α细胞中KATP通道的关闭来抑制葡萄糖调节的胰高血糖素分泌。
Glucagon secretion by pancreatic α-cells is triggered by hypoglycemia and suppressed by high glucose levels; impaired suppression of glucagon secretion is a hallmark of both type 1 and type 2 diabetes. Here, we show that α-cell glucokinase (Gck) plays a role in the control of glucagon secretion. Using mice with α-cell-specific inactivation of Gck (αGckKO mice), we find that glucokinase is required for the glucose-dependent increase in intracellular ATP/ADP ratio and the closure of KATP channels in α-cells and the suppression of glucagon secretion at euglycemic and hyperglycemic levels. αGckKO mice display hyperglucagonemia in the fed state, which is associated with increased hepatic gluconeogenic gene expression and hepatic glucose output capacity. In adult mice, fed hyperglucagonemia is further increased and glucose intolerance develops. Thus, glucokinase governs an α-cell metabolic pathway that suppresses secretion at or above normoglycemic levels; abnormal suppression of glucagon secretion deregulates hepatic glucose metabolism and, over time, induces a pre-diabetic phenotype. Glucagon secretion is promoted during hypoglycemia and inhibited by increased glucose levels. Here, Basco et al. show that glucokinase suppresses glucose-regulated glucagon secretion by modulating the intracellular ATP/ADP ratio and the closure of KATP channels in α-cells.