Glucagon lowers glycemia when β cells are active
Glucagon lowers glycemia when β cells are active
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DOI：
10.1172/jci.insight.129954
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发表时间：
2019-08-22
期刊：
影响因子：
8
通讯作者：
Campbell, Jonathan E.
中科院分区：
文献类型：
--
作者：
Capozzi, Megan E.;Wait, Jacob B.;Campbell, Jonathan E.
胰高血糖素和胰岛素通常被认为对血糖水平具有抵消作用。然而，最近的研究表明胰高血糖素具有激活β细胞和增强胰岛素分泌的生理作用。迄今为止，胰高血糖素的作用主要是在空腹或低血糖状态下研究的，但很明显，混合营养餐引起胰高血糖素和胰岛素的分泌，表明胰高血糖素也有助于餐后状态下的葡萄糖调节。我们假设在进食状态下观察到的升高的胰岛素水平将允许胰高血糖素刺激胰岛素分泌并降低血糖。事实上，在进食条件下给予外源性胰高血糖素确实强烈刺激胰岛素分泌并降低血糖。给予喂食Gcgr：Glp 1 r（β细胞-/-）小鼠的外源性胰高血糖素未能刺激胰岛素分泌或减少胰岛素分泌，表明促胰岛素胰高血糖素作用的重要性。内源性胰高血糖素在进食状态下降低血糖的作用通过给予丙氨酸（一种有效的胰高血糖素促分泌素）进行测试。丙氨酸在禁食WT小鼠或喂食Gcgr：Glp 1 r（β细胞-/-）小鼠中升高血糖，在这种情况下胰高血糖素无法刺激β细胞活性。然而，给予喂食的WT小鼠丙氨酸导致胰岛素水平降低，沿着胰岛素和胰高血糖素水平升高。总的来说，我们的数据支持这样一个模型，即胰高血糖素在进食状态下作为促胰岛素激素，补充而不是对抗胰岛素作用以维持正常。
Glucagon and insulin are commonly believed to have counteracting effects on blood glucose levels. However, recent studies have demonstrated that glucagon has a physiologic role to activate beta cells and enhance insulin secretion. To date, the actions of glucagon have been studied mostly in fasting or hypoglycemic states, yet it is clear that mixed-nutrient meals elicit secretion of both glucagon and insulin, suggesting that glucagon also contributes to glucose regulation in the postprandial state. We hypothesized that the elevated glycemia seen in the fed state would allow glucagon to stimulate insulin secretion and reduce blood glucose. In fact, exogenous glucagon given under fed conditions did robustly stimulate insulin secretion and lower glycemia. Exogenous glucagon given to fed Gcgr:Glp1r(beta cell-/-) mice failed to stimulate insulin secretion or reduce glycemia, demonstrating the importance of an insulinotropic glucagon effect. The action of endogenous glucagon to reduce glycemia in the fed state was tested with administration of alanine, a potent glucagon secretagogue. Alanine raised blood glucose in fasted WT mice or fed Gcgr:Glp1r(beta cell-/-) mice, conditions where glucagon is unable to stimulate beta cell activity. However, alanine given to fed WT mice produced a decrease in glycemia, along with elevated insulin and glucagon levels. Overall, our data support a model in which glucagon serves as an insulinotropic hormone in the fed state and complements rather than opposes insulin action to maintain euglycemia.