The role of GIP in α-cells and glucagon secretion.
The role of GIP in α-cells and glucagon secretion.
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DOI：
10.1016/j.peptides.2019.170213
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发表时间：
2020-03
期刊：
影响因子：
3
通讯作者：
Campbell JE
中科院分区：
文献类型：
--
作者：
El K;Campbell JE
葡萄糖依赖性促胰岛素多肽（GIP）是一种动物源性肽，在进食时分泌。GIP受体（GIPR）在参与代谢调节的许多细胞类型中表达，包括α细胞和β细胞。胰高血糖素和胰岛素对葡萄糖代谢起着巨大的控制作用。因此，胰岛中的GIP作用强烈决定了餐后状态的代谢控制。β细胞中GIPR活性的丧失是2型糖尿病（T2 D）的特征，其与餐后胰岛素分泌减少和高血糖症相关。关于α-细胞中GIPR活性或胰高血糖素分泌的控制知之甚少。在健康人群中，GIP以葡萄糖依赖性方式刺激胰高血糖素分泌，在较低血糖水平下活性增强。然而，GIP刺激胰高血糖素分泌，即使在患有T2 D的人中的高血糖症，这表明α细胞中不适当的GIPR活性有助于T2 D的发病机制。在此，我们回顾了描述GIP在α细胞中的作用和GIPR活性的文献，详细介绍了GIP如何调节胰高血糖素分泌的基础科学。我们还对比了GIP对健康人和T2 D人群胰高血糖素分泌的影响。最后，我们根据最近的工作重新定义胰高血糖素在葡萄糖稳态中的作用，将这些观察结果置于背景中，表明高胰高血糖素血症本身并不驱动高血糖症。随着纳入GIPR活性的T2 D新药的开发，很明显，有必要更好地了解β细胞以外的GIPR活性。这项工作强调了关注α细胞中GIPR的重要性。
Glucose-dependent insulinotropic polypeptide (GIP) is an intestinally derived peptide that is secreted in response to feeding. The GIP receptor (GIPR) is expressed in many cell types involved in the regulation of metabolism, including α- and β-cells. Glucagon and insulin exert tremendous control over glucose metabolism. Thus, GIP action in islets strongly dictates metabolic control in the postprandial state. Loss of GIPR activity in β-cells is a characteristic of type 2 diabetes (T2D) which associates with reduced postprandial insulin secretion and hyperglycemia. Less is known about GIPR activity in α-cells or the control of glucagon secretion. GIP stimulates glucagon secretion in a glucose-dependent manner in healthy people, with enhanced activity at lower glycemia. However, GIP stimulates glucagon secretion even at hyperglycemia in people with T2D, suggesting that inappropriate GIPR activity in α-cells contributes to the pathogenesis of T2D. Here, we review the literature describing GIP action and GIPR activity in the α-cell, detailing the basic science that has shaped the view of how GIP regulates glucagon secretion. We also contrast the effects of GIP on glucagon secretion in healthy and T2D people. Finally, we contextualize these observations in light of recent work that redefines the role of glucagon in glucose homeostasis, suggesting that hyperglucagonemia per se does not drive hyperglycemia. As new medications for T2D that incorporate GIPR activity are being developed, it is clear that a better understanding of GIPR activity beyond the β-cell is necessary. This work highlights the importance of focusing on the GIPR in α-cells.
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