Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP
Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP
复制标题
DOI：
10.1152/ajpendo.00344.2014
复制
发表时间：
2015-01-15
影响因子：
5.1
通讯作者：
Piston, David W.
中科院分区：
文献类型：
--
作者：
Elliott, Amicia D.;Ustione, Alessandro;Piston, David W.
葡萄糖抑制的胰高血糖素从胰岛α细胞分泌的失调是糖尿病病理学和代谢疾病的关键组成部分。我们显示了一种以前未表征的人和鼠胰岛中胰高血糖素抑制的[Ca 2 +]（i）-非依赖性机制，从而降低cAMP和PKA信号传导。这种降低是由生长抑素和胰岛素的组合驱动的，生长抑素通过SSTR 2的G α（i）亚基抑制腺苷酸环化酶产生cAMP，胰岛素通过其受体激活磷酸二酯酶3B并降解胞质cAMP。我们的数据表明，生长抑素和胰岛素信号传导都需要抑制人和鼠α细胞的cAMP/PKA和胰高血糖素分泌，并且这两种信号传导机制的组合足以减少分离的α细胞以及胰岛的胰高血糖素分泌。因此，我们得出结论，生长抑素和胰岛素一起是葡萄糖抑制胰高血糖素分泌和功能的关键旁分泌介质，降低cAMP/PKA信号与葡萄糖增加。
The dysregulation of glucose-inhibited glucagon secretion from the pancreatic islet alpha-cell is a critical component of diabetes pathology and metabolic disease. We show a previously uncharacterized [Ca2+] (i)-independent mechanism of glucagon suppression in human and murine pancreatic islets whereby cAMP and PKA signaling are decreased. This decrease is driven by the combination of somatostatin, which inhibits adenylyl cyclase production of cAMP via the G alpha(i) subunit of the SSTR2, and insulin, which acts via its receptor to activate phosphodiesterase 3B and degrade cytosolic cAMP. Our data indicate that both somatostatin and insulin signaling are required to suppress cAMP/PKA and glucagon secretion from both human and murine alpha-cells, and the combination of these two signaling mechanisms is sufficient to reduce glucagon secretion from isolated alpha-cells as well as islets. Thus, we conclude that somatostatin and insulin together are critical paracrine mediators of glucose-inhibited glucagon secretion and function by lowering cAMP/PKA signaling with increasing glucose.