A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release
A role for intestinal endocrine cell-expressed g protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release
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DOI：
10.1210/en.2007-0966
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发表时间：
2008-05-01
期刊：
影响因子：
4.8
通讯作者：
Leonard, James
中科院分区：
文献类型：
--
作者：
Chu, Zhi-Liang;Carroll, Chris;Leonard, James
我们最近发现，G蛋白偶联受体119（GPR 119）（也称为葡萄糖依赖性促胰岛素受体）的激活通过直接cAMP介导的胰腺β细胞中葡萄糖依赖性胰岛素释放的增强来改善葡萄糖稳态。在这里，我们表明，GPR 119也刺激肠促胰岛素激素的释放，从而可能通过这种额外的机制来调节葡萄糖稳态。发现GPR 119 mRNA在产生葡萄糖依赖性促胰岛素肽和胰高血糖素样肽（GLP）-1的肠亚区中以显著水平表达。此外，原位杂交研究表明，大多数GLP-1产生细胞共表达GPR 119 mRNA。在GLUTag细胞（一种已建立的肠L细胞功能模型）中，强效GPR 119激动剂AR 231453刺激cAMP蓄积和GLP-1释放。当在小鼠中给药时，AR 231453在口服葡萄糖递送后2分钟内增加活性GLP-1水平，并显著增加总葡萄糖依赖性促胰岛素肽水平。用毒蜥外泌肽（9-39）阻断GLP-1受体信号传导降低了AR 231453改善小鼠葡萄糖耐量的能力。相反，相对于任一药物单独给药，AR 231453和DPP-4抑制剂西格列汀联合给药野生型小鼠显著增加了血浆GLP-1水平和口服葡萄糖耐量。在缺乏GPR 119的小鼠中，没有看到这种增强。因此，GPR 119通过作用于肠内分泌细胞以及胰腺β细胞来调节葡萄糖耐量。这些数据还表明，联合刺激肠促胰岛素释放和保护肠促胰岛素降解可能是一种有效的抗糖尿病策略。
We recently showed that activation of G protein-coupled receptor 119 (GPR119) (also termed glucose dependent insulinotropic receptor) improves glucose homeostasis via direct cAMP-mediated enhancement of glucose-dependent insulin release in pancreatic beta-cells. Here we show that GPR119 also stimulates incretin hormone release and thus may regulate glucose homeostasis by this additional mechanism. GPR119 mRNA was found to be expressed at significant levels in intestinal subregions that produce glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1. Furthermore, in situ hybridization studies indicated that most GLP-1-producing cells coexpress GPR119 mRNA. In GLUTag cells, a well-established model of intestinal L-cell function, the potent GPR119 agonist AR231453 stimulated cAMP accumulation and GLP-1 release. When administered in mice, AR231453 increased active GLP-1 levels within 2 min after oral glucose delivery and substantially enhanced total glucose-dependent insulinotropic peptide levels. Blockade of GLP-1 receptor signaling with exendin(9-39) reduced the ability of AR231453 to improve glucose tolerance in mice. Conversely, combined administration of AR231453 and the DPP-4 inhibitor sitagliptin to wild-type mice significantly amplified both plasma GLP-1 levels and oral glucose tolerance, relative to either agent alone. In mice lacking GPR119, no such enhancement was seen. Thus, GPR119 regulates glucose tolerance by acting on intestinal endocrine cells as well as pancreatic beta-cells. These data also suggest that combined stimulation of incretin hormone release and protection against incretin hormone degradation may be an effective antidiabetic strategy.