Raju Bharathi, Cryer Philip E
Division of Endocrinology, Metabolism and Lipid Research, General Clinical Research Center, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110, USA.
Diabetes. 2005 Mar;54(3):757-64. doi: 10.2337/diabetes.54.3.757.
The intraislet insulin hypothesis for the signaling of the glucagon secretory response to hypoglycemia states that a decrease in arterial glucose --> a decrease in beta-cell insulin secretion --> a decrease in tonic alpha-cell inhibition by insulin --> an increase in alpha-cell glucagon secretion. To test this hypothesis in humans, a hyperinsulinemic- euglycemic ( approximately 5.0 mmol/l [90 mg/dl] x 2 h) and then a hypoglycemic ( approximately 3.0 mmol/l [55 mg/dl] x 2 h) clamp was performed in 14 healthy young adults on two occasions, once with oral administration of the ATP-sensitive potassium channel agonist diazoxide to selectively suppress baseline insulin secretion and once with the administration of a placebo. The decrement in plasma C-peptide during the induction of hypoglycemia was reduced by approximately 50% in the diazoxide clamps (from 0.3 +/- 0.0 to 0.1 +/- 0.0 nmol/l [0.8 +/- 0.1 to 0.4 +/- 0.1 ng/ml]) compared with the placebo clamps (from 0.4 +/- 0.0 to 0.1 +/- 0.0 nmol/l [1.2 +/- 0.1 to 0.4 +/- 0.1 ng/ml]) (P = 0.0015). This reduction of the decrement in intraislet insulin during induction of hypoglycemia caused an approximately 50% reduction (P = 0.0010) of the increase in plasma glucagon in the diazoxide clamps (from 29 +/- 3 to 35 +/- 2 pmol/l [102 +/- 9 to 123 +/- 8 pg/ml]) compared with the placebo clamps (from 28 +/- 2 to 43 +/- 5 pmol/l [98 +/- 7 to 151 +/- 16 pg/ml]). Baseline glucagon levels, the glucagon response to intravenous arginine, and the autonomic (adrenomedullary, sympathetic neural, and parasympathetic neural) responses to hypoglycemia were not altered by diazoxide. These data indicate that a decrease in intraislet insulin is a signal for the glucagon secretory response to hypoglycemia in healthy humans. The absence of that signal plausibly explains the loss of the glucagon response to falling plasma glucose concentrations, a key feature of the pathogenesis of iatrogenic hypoglycemia, in insulin-deficient (type 1 and advanced type 2) diabetes.
胰岛内胰岛素假说认为，低血糖时胰高血糖素分泌反应的信号传导过程为：动脉血糖降低→β细胞胰岛素分泌减少→胰岛素对α细胞的紧张性抑制减弱→α细胞胰高血糖素分泌增加。为在人体中验证这一假说，对14名健康年轻成年人进行了两次钳夹试验，一次是高胰岛素-正常血糖（约5.0 mmol/L [90 mg/dl]，持续2小时），随后是低血糖（约3.0 mmol/L [55 mg/dl]，持续2小时），一次口服ATP敏感性钾通道激动剂二氮嗪以选择性抑制基础胰岛素分泌，另一次给予安慰剂。与安慰剂钳夹试验（从0.4±0.0降至0.1±0.0 nmol/L [1.2±0.1至0.4±0.1 ng/ml]）相比，二氮嗪钳夹试验中低血糖诱导期间血浆C肽的下降幅度降低了约50%（从0.3±0.0降至0.1±0.0 nmol/L [0.8±0.1至0.4±0.1 ng/ml]）（P = 0.0015）。低血糖诱导期间胰岛内胰岛素下降幅度的减小，使得二氮嗪钳夹试验中血浆胰高血糖素升高幅度降低了约50%（P = 0.0010）（从29±3升至35±2 pmol/L [102±9至123±8 pg/ml]），而安慰剂钳夹试验中则从28±2升至43±5 pmol/L [98±7至151±16 pg/ml]）。二氮嗪未改变基础胰高血糖素水平、胰高血糖素对静脉注射精氨酸的反应以及对低血糖的自主神经（肾上腺髓质、交感神经和副交感神经）反应。这些数据表明，胰岛内胰岛素减少是健康人体中胰高血糖素对低血糖分泌反应的信号。在胰岛素缺乏（1型和晚期2型）糖尿病中，该信号的缺失可能解释了胰高血糖素对血浆葡萄糖浓度下降反应的丧失，这是医源性低血糖发病机制的一个关键特征。
