Glucagon-like Peptide 1 Receptor Signaling in Acinar Cells Causes Growth-Dependent Release of Pancreatic Enzymes
Glucagon-like Peptide 1 Receptor Signaling in Acinar Cells Causes Growth-Dependent Release of Pancreatic Enzymes
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DOI：
10.1016/j.celrep.2016.11.051
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发表时间：
2016-12-13
期刊：
影响因子：
8.8
通讯作者：
Holst, Jens J.
中科院分区：
文献类型：
--
作者：
Albrechtsen, Nicolai J. Wewer;Albrechtsen, Reidar;Holst, Jens J.
基于肠促胰岛素的疗法被广泛用于2型糖尿病，现在也用于肥胖症，但它们与胰腺酶的血浆水平升高相关，并且可能适度增加急性胰腺炎的风险。然而，很少有人知道肠促胰岛素激素胰高血糖素样肽1（GLP-1）的外分泌胰腺的影响。在此，我们鉴定了胰腺腺泡上的GLP-1受体，并分析了受体活化对人类、啮齿动物、分离的腺泡和胰腺外分泌细胞系的影响。GLP-1不直接刺激淀粉酶或脂肪酶释放。然而，我们发现GLP-1诱导表皮生长因子受体磷酸化和Foxo 1活化，导致细胞生长伴随酶释放。我们的工作揭示了GLP-1诱导的胰腺外分泌信号通路，并表明GLP-1受体激动剂治疗受试者的淀粉酶和脂肪酶水平升高反映了适应性生长，而不是早期胰腺炎。
Incretin-based therapies are widely used for type 2 diabetes and now also for obesity, but they are associated with elevated plasma levels of pancreatic enzymes and perhaps a modestly increased risk of acute pancreatitis. However, little is known about the effects of the incretin hormone glucagon-like peptide 1 (GLP-1) on the exocrine pancreas. Here, we identify GLP-1 receptors on pancreatic acini and analyze the impact of receptor activation in humans, rodents, isolated acini, and cell lines from the exocrine pancreas. GLP-1 did not directly stimulate amylase or lipase release. However, we saw that GLP-1 induces phosphorylation of the epidermal growth factor receptor and activation of Foxo1, resulting in cell growth with concomitant enzyme release. Our work uncovers GLP-1-induced signaling pathways in the exocrine pancreas and suggests that increases in amylase and lipase levels in subjects treated with GLP-1 receptor agonists reflect adaptive growth rather than early-stage pancreatitis.