Xu Stella F S, Andersen Daniel B, Izarzugaza Jose M G, Kuhre Rune E, Holst Jens J
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Acta Physiol (Oxf). 2020 Jul;229(3):e13464. doi: 10.1111/apha.13464. Epub 2020 Mar 25.
It is debated whether the inhibition of glucagon secretion by glucose results from direct effects of glucose on the α-cell (intrinsic regulation) or by paracrine effects exerted by beta- or delta-cell products.
To study this in a more physiological model than isolated islets, we perfused isolated rat pancreases and measured glucagon, insulin and somatostatin secretion in response to graded increases in perfusate glucose concentration (from 3.5 to 4, 5, 6, 7, 8, 10, 12 mmol/L) as well as glucagon responses to blockage/activation of insulin/GABA/somatostatin signalling with or without addition of glucose.
Glucagon secretion was reduced by about 50% (compared to baseline secretion at 3.5 mmol/L) within minutes after increasing glucose from 4 to 5 mmol/L (P < .01, n = 13). Insulin secretion was increased minimally, but significantly, compared to baseline (3.5 mmol/L) at 4 mmol/L, whereas somatostatin secretion was not significantly increased from baseline until 7 mmol/L. Hereafter secretion of both increased gradually up to 12 mmol/L glucose. Neither recombinant insulin (1 µmol/L), GABA (300 µmol/L) or the insulin-receptor antagonist S961 (at 1 µmol/L) affected basal (3.5 mmol/L) or glucose-induced (5.0 mmol/L) attenuation of glucagon secretion (n = 7-8). Somatostatin-14 attenuated glucagon secretion by ~ 95%, and blockage of somatostatin-receptor (SSTR)-2 or combined blockage of SSTR-2, -3 and -5 by specific antagonists increased glucagon output (at 3.5 mmol/L glucose) and prevented glucose-induced (from 3.5 to 5.0 mmol/L) suppression of secretion.
Somatostatin is a powerful and tonic inhibitor of glucagon secretion from the rat pancreas and is required for glucose to inhibit glucagon secretion.
葡萄糖对胰高血糖素分泌的抑制作用是源于葡萄糖对α细胞的直接作用（内在调节），还是由β细胞或δ细胞产物产生的旁分泌作用，目前仍存在争议。
为了在比分离胰岛更具生理学意义的模型中研究这一问题，我们对分离的大鼠胰腺进行灌注，并测量了胰高血糖素、胰岛素和生长抑素的分泌，以响应灌注液葡萄糖浓度的分级增加（从3.5到4、5、6、7、8、10、12 mmol/L），以及在添加或不添加葡萄糖的情况下，胰高血糖素对胰岛素/GABA/生长抑素信号通路阻断/激活的反应。
将葡萄糖浓度从4 mmol/L提高到5 mmol/L后几分钟内，胰高血糖素分泌减少了约50%（与3.5 mmol/L时的基础分泌相比）（P <.01，n = 13）。与4 mmol/L时的基础水平（3.5 mmol/L）相比，胰岛素分泌略有增加，但具有统计学意义，而生长抑素分泌直到7 mmol/L时才较基础水平有显著增加。此后，二者的分泌在葡萄糖浓度达到12 mmol/L之前逐渐增加。重组胰岛素（1 μmol/L）、GABA（300 μmol/L）或胰岛素受体拮抗剂S961（1 μmol/L）均未影响基础状态（3.5 mmol/L）或葡萄糖诱导（5.0 mmol/L）的胰高血糖素分泌减弱（n = 7 - 8）。生长抑素-14使胰高血糖素分泌减弱约95%，特异性拮抗剂阻断生长抑素受体（SSTR）-2或联合阻断SSTR-2、-3和-5可增加胰高血糖素分泌（在3.5 mmol/L葡萄糖时），并阻止葡萄糖诱导（从3.5到5.0 mmol/L）的分泌抑制。
生长抑素是大鼠胰腺胰高血糖素分泌的一种强大且持续性的抑制剂，是葡萄糖抑制胰高血糖素分泌所必需的。
