Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model.
Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model.
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作者：
Gier B;Matveyenko AV;Kirakossian D;Dawson D;Dry SM;Butler PC
胰腺导管腺体(PDG)被认为是引起胰腺上皮内瘤变(Panin)的原因。经胰升糖素样肽(GLP)-1类似物exendin-4处理12周后，大鼠PDGs扩张，伴有粘液化生和类似低度Panin的柱状细胞异型性。在Pdx1-Cre；LSL-KrasG12D小鼠的胰腺中，exendin-4导致外分泌结构的破坏和慢性胰腺炎粘液化生的加速，并增加了小鼠Panin病变的形成。啮齿动物和人胰腺的PDGs和Panin病变表达GLP-1受体。Exendin-4诱导人胰腺管细胞增殖信号通路，cAMP-蛋白激酶A和丝裂原活化蛋白激酶磷酸化cAMP反应元件结合蛋白，并增加细胞周期蛋白D1的表达。这些GLP-1效应在Kras的激活突变存在时更为明显，并被二甲双胍抑制。这些数据表明，GLP-1类似物治疗可以诱导外分泌胰腺的局灶性增殖，在外分泌异常的情况下，可能会加速肿瘤性Panin病变的形成，并加重慢性胰腺炎。
Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, for 12 weeks induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-KrasG12D mice, exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, cAMP–protein kinase A and mitogen-activated protein kinase phosphorylation of cAMP-responsive element-binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis.
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影响因子：
8.2
作者：
Butler, A. E.;Galasso, R.;Matveyenko, A.;Rizza, R. A.;Dry, S.;Butler, P. C.
通讯作者：
Butler, P. C.
影响因子：
16.2
作者：
Fineman, MS;Bicsak, TA;Baron, AD
通讯作者：
Baron, AD
影响因子：
4
作者：
Friedrichsen, BN;Neubauer, N;Moldrup, A
通讯作者：
Moldrup, A
影响因子：
50.3
作者：
Hingorani, SR;Petricoin, EF;Tuveson, DA
通讯作者：
Tuveson, DA
影响因子：
16.2
作者：
Aschner, Pablo;Kipnes, Mark S.;Williams-Herman, Debora E.
通讯作者：
Williams-Herman, Debora E.