Vieira E, Salehi A, Gylfe E
Department of Medical Cell Biology, Uppsala University, BMC Box 571, SE-751 23, Uppsala, Sweden.
Diabetologia. 2007 Feb;50(2):370-9. doi: 10.1007/s00125-006-0511-1. Epub 2006 Nov 29.
AIMS/HYPOTHESIS: The mechanisms by which glucose regulates glucagon release are poorly understood. The present study aimed to clarify the direct effects of glucose on the glucagon-releasing alpha cells and those effects mediated by paracrine islet factors.
Glucagon, insulin and somatostatin release were measured from incubated mouse pancreatic islets and the cytoplasmic Ca(2+) concentration (Ca(2+)) recorded in isolated mouse alpha cells.
Glucose inhibited glucagon release with maximal effect at 7 mmol/l. Since this concentration corresponded to threshold stimulation of insulin secretion, it is unlikely that inhibition of glucagon secretion is mediated by beta cell factors. Although somatostatin secretion data seemed consistent with a role of this hormone in glucose-inhibited glucagon release, a somatostatin receptor type 2 antagonist stimulated glucagon release without diminishing the inhibitory effect of glucose. In islets exposed to tolbutamide plus 8 mmol/l K(+), glucose inhibited glucagon secretion without stimulating the release of insulin and somatostatin, indicating a direct inhibitory effect on the alpha cells that was independent of ATP-sensitive K(+) channels. Glucose lowered Ca(2+) of individual alpha cells independently of somatostatin and beta cell factors (insulin, Zn(2+) and gamma-aminobutyric acid). Glucose suppression of glucagon release was prevented by inhibitors of the sarco(endo)plasmic reticulum Ca(2+)-ATPase, which abolished the Ca(2+)-lowering effect of glucose on isolated alpha cells.
CONCLUSIONS/INTERPRETATION: Beta cell factors or somatostatin do not seem to mediate glucose inhibition of glucagon secretion. We instead propose that glucose has a direct inhibitory effect on mouse alpha cells by suppressing a depolarising Ca(2+) store-operated current.
目的/假设：葡萄糖调节胰高血糖素释放的机制尚不清楚。本研究旨在阐明葡萄糖对释放胰高血糖素的α细胞的直接作用以及旁分泌胰岛因子介导的那些作用。
从小鼠胰岛孵育物中测量胰高血糖素、胰岛素和生长抑素的释放，并记录分离的小鼠α细胞中的细胞质Ca(2+)浓度（[Ca(2+)]i）。
葡萄糖抑制胰高血糖素释放，在7 mmol/l时效果最大。由于该浓度对应于胰岛素分泌的阈值刺激，因此胰高血糖素分泌的抑制不太可能由β细胞因子介导。尽管生长抑素分泌数据似乎与该激素在葡萄糖抑制的胰高血糖素释放中的作用一致，但2型生长抑素受体拮抗剂刺激了胰高血糖素释放，而没有减弱葡萄糖的抑制作用。在暴露于甲苯磺丁脲加8 mmol/l K(+)的胰岛中，葡萄糖抑制胰高血糖素分泌，而不刺激胰岛素和生长抑素的释放，表明对α细胞有直接抑制作用，且独立于ATP敏感性钾通道。葡萄糖降低单个α细胞的[Ca(2+)]i，独立于生长抑素和β细胞因子（胰岛素、Zn(2+)和γ-氨基丁酸）。肌浆网Ca(2+)-ATP酶抑制剂可阻止葡萄糖对胰高血糖素释放的抑制作用，该抑制剂消除了葡萄糖对分离的α细胞的[Ca(2+)]i降低作用。
结论/解读：β细胞因子或生长抑素似乎不介导葡萄糖对胰高血糖素分泌的抑制作用。相反，我们提出葡萄糖通过抑制去极化的Ca(2+)储存操纵电流对小鼠α细胞有直接抑制作用。
