Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.
Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.
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DOI：
10.7554/elife.72919
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发表时间：
2021-11-17
期刊：
影响因子：
7.7
通讯作者：
Briant LJ
中科院分区：
文献类型：
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作者：
Kim A;Knudsen JG;Madara JC;Benrick A;Hill TG;Abdul Kadir L;Kellard JA;Mellander L;Miranda C;Lin H;James T;Suba K;Spigelman AF;Wu Y;MacDonald PE;Wernstedt Asterholm I;Magnussen T;Christensen M;Vilsbøll T;Salem V;Knop FK;Rorsman P;Lowell BB;Briant LJ
胰岛素诱导的低血糖是1型糖尿病（T1 D）的主要治疗障碍。因此，重要的是我们要了解调节胰高血糖素循环水平的机制。在进食和燃料缺乏状态之间生理上发生的浓度范围内改变葡萄糖（8至4 mM）对灌注的小鼠胰腺或分离的小鼠胰岛（体外）中的胰高血糖素分泌没有显著影响，但与血浆胰高血糖素的显著增加相关。升高循环胰高血糖素的全身性因素的身份仍然未知。在这里，我们表明，精氨酸加压素（AVP），从垂体后叶分泌，刺激胰高血糖素分泌。α细胞表达高水平的血管加压素1b受体（V1 bR）基因（Avpr 1b）。体内AVP神经元的激活增加了循环和肽素（AVP前体肽的C-末端片段）并增加了血糖;胰高血糖素受体或V1 bR的药理学拮抗作用阻断了这种作用。AVP还介导外源性胰岛素和2-脱氧-D-葡萄糖引起的低血糖对胰高血糖素分泌的刺激作用。我们发现，延髓的A1/C1神经元驱动AVP神经元激活胰岛素诱导的低血糖反应。AVP注射增加了α细胞（植入眼前房）中的细胞质Ca 2+和胰高血糖素释放。低血糖还增加人体内AVP/和肽素的循环水平，并且这种激素刺激人胰岛分泌胰高血糖素。在T1 D患者中，低血糖未能增加和肽素和胰高血糖素。这些发现表明AVP是胰高血糖素分泌的生理系统调节剂，并且该机制在T1 D中受损。
Insulin-induced hypoglycemia is a major treatment barrier in type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro), and yet associates with dramatic increases in plasma glucagon. The identity of the systemic factor(s) that elevates circulating glucagon remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Alpha-cells express high levels of the vasopressin 1b receptor (V1bR) gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or V1bR. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. AVP injection increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP/copeptin in humans and this hormone stimulates glucagon secretion from human islets. In patients with T1D, hypoglycemia failed to increase both copeptin and glucagon. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.