Basco Davide, Zhang Quan, Salehi Albert, Tarasov Andrei, Dolci Wanda, Herrera Pedro, Spiliotis Ioannis, Berney Xavier, Tarussio David, Rorsman Patrik, Thorens Bernard
Center for Integrative Genomics, University of Lausanne, 1015, Lausanne, Switzerland.
Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.
Nat Commun. 2018 Feb 7;9(1):546. doi: 10.1038/s41467-018-03034-0.
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 K 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.
胰腺α细胞分泌胰高血糖素由低血糖触发，并受高血糖水平抑制；胰高血糖素分泌抑制受损是1型和2型糖尿病的一个标志。在此，我们表明α细胞葡萄糖激酶（Gck）在胰高血糖素分泌的控制中起作用。利用α细胞特异性敲除Gck的小鼠（αGckKO小鼠），我们发现葡萄糖激酶对于α细胞内ATP/ADP比值的葡萄糖依赖性增加、K通道的关闭以及在正常血糖和高血糖水平下抑制胰高血糖素分泌是必需的。αGckKO小鼠在进食状态下表现出高胰高血糖素血症，这与肝脏糖异生基因表达增加和肝脏葡萄糖输出能力增强有关。在成年小鼠中，进食后高胰高血糖素血症进一步增加，并出现葡萄糖不耐受。因此，葡萄糖激酶控制着一种α细胞代谢途径，该途径在正常血糖水平或以上抑制分泌；胰高血糖素分泌的异常抑制会使肝脏葡萄糖代谢失调，并随着时间的推移诱发糖尿病前期表型。
