Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes
Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes
复制标题
胰高血糖素受体拮抗剂通过促进 2 型糖尿病中肠道 L 细胞增殖和 GLP-1 产生来上调循环 GLP-1 水平
DOI：
10.1136/bmjdrc-2019-001025
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发表时间：
2020-01-01
影响因子：
4.1
通讯作者：
Hong, Tianpei
中科院分区：
文献类型：
--
作者：
Lang, Shan;Yang, Jin;Hong, Tianpei
Objectigglucagon受体（GCGR）阻塞可改善血糖控制，并增加糖尿病动物和人类中循环胰高血糖素样肽-1（GLP-1）水平。据报道，GLP-1升高参与GCGR阻塞的降血糖作用。然而，该海拔的来源仍有待澄清。研究设计和方法2.59，一种人GCGR单克隆抗体（MAB），在DB/DB小鼠和高脂饮食+链霉菌素（HFD/STZ）诱导的2型2型糖尿病（T2D）小鼠中，在DB/DB小鼠中管理12周。在治疗过程中评估了血糖，葡萄糖耐受性和血浆GLP-1。处死小鼠后，检测到肠道长度，上皮面积和L细胞数和增殖。在小鼠L细胞系谷格细胞以及原代小鼠和人肠细胞中测量细胞增殖和GLP-1的产生。此外，使用GLP-1受体（GLP-1R）拮抗剂或蛋白激酶A（PKA）抑制剂在谷塔细胞中用于确定所涉及的信号传导途径。与GCGR MAB降低血糖水平，葡萄糖耐受性的降低，葡萄糖耐受性降低，并提高了DB/DB/DB/STZ-STZ-stec-ind tecd的葡萄糖耐受性和升高的血浆GLP-1水平。此外，该处理促进了L细胞增殖和LK细胞的扩张，并增加了这两只T2D小鼠的肠道长度，上皮面积和L细胞数。同样，我们的体外研究表明，GCGR MAB促进了谷塔细胞中的L细胞增殖，并增加了GLP-1的产生，而原代小鼠和人肠细胞。此外，GLP-1R拮抗剂或PKA抑制剂都会降低GCGR mAb对L细胞增殖和GLP-1产生的影响。结论性通过GCGR mAB升高的GLP-1水平升高的主要是由于肠道L细胞增殖增殖和GLP-1的产生，可以通过GLP-1R/PKA Signaling pathrowe进行介导。因此，GCGR MAB代表了改善血糖控制并恢复T2D中GLP-1产生受损的有前途的策略。
Objective Glucagon receptor (GCGR) blockage improves glycemic control and increases circulating glucagon-like peptide-1 (GLP-1) level in diabetic animals and humans. The elevated GLP-1 has been reported to be involved in the hypoglycemic effect of GCGR blockage. However, the source of this elevation remains to be clarified. Research design and methods REMD 2.59, a human GCGR monoclonal antibody (mAb), was administrated for 12 weeks in db/db mice and high-fat diet+streptozotocin (HFD/STZ)-induced type 2 diabetic (T2D) mice. Blood glucose, glucose tolerance and plasma GLP-1 were evaluated during the treatment. The gut length, epithelial area, and L-cell number and proliferation were detected after the mice were sacrificed. Cell proliferation and GLP-1 production were measured in mouse L-cell line GLUTag cells, and primary mouse and human enterocytes. Moreover, GLP-1 receptor (GLP-1R) antagonist or protein kinase A (PKA) inhibitor was used in GLUTag cells to determine the involved signaling pathways. Results Treatment with the GCGR mAb lowered blood glucose level, improved glucose tolerance and elevated plasma GLP-1 level in both db/db and HFD/STZ-induced T2D mice. Besides, the treatment promoted L-cell proliferation and LK-cell expansion, and increased the gut length, epithelial area and L-cell number in these two T2D mice. Similarly, our in vitro study showed that the GCGR mAb promoted L-cell proliferation and increased GLP-1 production in GLUTag cells, and primary mouse and human enterocytes. Furthermore, either GLP-1R antagonist or PKA inhibitor diminished the effects of GCGR mAb on L-cell proliferation and GLP-1 production. Conclusions The elevated circulating GLP-1 level by GCGR mAb is mainly due to intestinal L-cell proliferation and GLP-1 production, which may be mediated via GLP-1R/PKA signaling pathways. Therefore, GCGR mAb represents a promising strategy to improve glycemic control and restore the impaired GLP-1 production in T2D.