Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes.
Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes.
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DOI：
10.1016/j.cmet.2013.10.014
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发表时间：
2013-12-03
期刊：
影响因子：
29
通讯作者：
Rorsman P
中科院分区：
文献类型：
--
作者：
Zhang Q;Ramracheya R;Lahmann C;Tarasov A;Bengtsson M;Braha O;Braun M;Brereton M;Collins S;Galvanovskis J;Gonzalez A;Groschner LN;Rorsman NJ;Salehi A;Travers ME;Walker JN;Gloyn AL;Gribble F;Johnson PR;Reimann F;Ashcroft FM;Rorsman P
胰高血糖素由胰岛α细胞分泌，是主要的高血糖激素。在糖尿病中，高血糖时胰高血糖素分泌不受抑制，加剧胰岛素分泌不足的后果，低血糖时胰高血糖素分泌不足，可能导致致命的低血糖。其因果机制尚不清楚。本研究表明，在低血糖状态下，α细胞katp通道活性非常低，高血糖通过细胞内ATP/ADP升高导致完全抑制。这产生膜去极化和电压依赖性的Na+通道失活参与动作电位放电，通过降低动作电位高度和Ca2+进入，抑制胰高血糖素的分泌。增加KATP通道活性的操作，如代谢抑制，模拟与糖尿病相关的胰高血糖素分泌缺陷。低浓度的KATP通道阻滞剂甲苯丁胺部分恢复2型糖尿病器官供体胰岛中葡萄糖调节的胰高血糖素分泌。这些数据表明，在2型糖尿病中，KATP通道的代谢控制受损是胰高血糖素分泌的葡萄糖调节缺陷的基础。KATP通道关闭刺激胰岛素分泌但抑制胰高血糖素释放α细胞去极化减少电压门控Ca2+进入和胰高血糖素释放激活KATP通道突变损害小鼠胰高血糖素释放KATP通道关闭纠正2型糖尿病胰岛胰高血糖素分泌缺陷
Glucagon, secreted by pancreatic islet α cells, is the principal hyperglycemic hormone. In diabetes, glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia. The causal mechanisms remain unknown. Here we show that α cell KATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na+ channels involved in action potential firing that, via reduced action potential height and Ca2+ entry, suppresses glucagon secretion. Maneuvers that increase KATP channel activity, such as metabolic inhibition, mimic the glucagon secretory defects associated with diabetes. Low concentrations of the KATP channel blocker tolbutamide partially restore glucose-regulated glucagon secretion in islets from type 2 diabetic organ donors. These data suggest that impaired metabolic control of the KATP channels underlies the defective glucose regulation of glucagon secretion in type 2 diabetes. KATP channel closure stimulates insulin secretion but inhibits glucagon release α cell depolarization reduces voltage-gated Ca2+ entry and glucagon release An activating KATP channel mutation impairs glucagon release in mice KATP channel closure corrects glucagon secretion defect in type 2 diabetic islets
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