Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
Cell Metab. 2013 Dec 3;18(6):871-82. doi: 10.1016/j.cmet.2013.10.014.
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 Ca(2+) 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.
胰脏胰岛α细胞分泌的胰高血糖素是主要的升血糖激素。在糖尿病中，高血糖时胰高血糖素分泌不能被抑制，加剧了胰岛素分泌不足的后果，而在低血糖时分泌又不足，可能导致致命性低血糖。其因果机制仍不清楚。本研究显示，低血糖时α细胞 KATP 通道活性非常低，而高血糖通过升高细胞内 ATP/ADP 比值导致完全抑制。这导致参与动作电位发放的 Na+通道去极化和电压依赖性失活，通过降低动作电位幅度和 Ca2+内流，抑制胰高血糖素分泌。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 通道阻断剂甲苯磺丁脲可部分恢复 2 型糖尿病供体胰岛中葡萄糖调节的胰高血糖素分泌。这些数据表明，2 型糖尿病中胰高血糖素分泌的葡萄糖调节缺陷的基础是 KATP 通道代谢控制受损。
