A role for β-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release
A role for β-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release
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DOI：
10.1210/en.2006-1608
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发表时间：
2007-06-01
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;Jones, Robert M.;Leonard, James
胰腺β细胞功能障碍是2型糖尿病发病机制中的一个标志性事件。注射胰高血糖素样肽1 （GLP-1）受体的肽激动剂作为抗糖尿病药物具有显著的前景，因为它们能够增加葡萄糖依赖性胰岛素的释放并保持胰腺β细胞质量。这些作用是通过β细胞GLP-1受体刺激cAMP介导的。我们报道了G α (s)偶联受体GPR119主要局限于胰岛产生胰岛素的β细胞。此外，我们在这里表明GPR119作为葡萄糖依赖性胰岛素受体起作用。与GLP-1和其他介导葡萄糖依赖性胰岛素释放增强的肽的受体不同，GPR119适合于开发有效的、口服活性的小分子激动剂。gpr119特异性激动剂AR231453显著增加HIT-T15细胞和啮齿动物胰岛的cAMP积累和胰岛素释放。在这两种情况下，GPR119的缺失使AR231453失去活性。AR231453还能增强体内葡萄糖依赖型胰岛素释放，改善野生型小鼠的口服葡萄糖耐量，但在gpr119缺陷小鼠中无此作用。糖尿病KK/A(y)小鼠也对AR231453有高度反应。口服活性GPR119激动剂可能作为一种新的血糖依赖性降糖药物提供了重要的前景。
Pancreatic beta-cell dysfunction is a hallmark event in the pathogenesis of type 2 diabetes. Injectable peptide agonists of the glucagon-like peptide 1 (GLP-1) receptor have shown significant promise as antidiabetic agents by virtue of their ability to amplify glucose-dependent insulin release and preserve pancreatic beta-cell mass. These effects are mediated via stimulation of cAMP through beta-cell GLP-1 receptors. We report that the G alpha(s)-coupled receptor GPR119 is largely restricted to insulin-producing beta-cells of pancreatic islets. Additionally, we show here that GPR119 functions as a glucose-dependent insulinotropic receptor. Unlike receptors for GLP-1 and other peptides that mediate enhanced glucose-dependent insulin release, GPR119 was suitable for the development of potent, orally active, small-molecule agonists. The GPR119-specific agonist AR231453 significantly increased cAMP accumulation and insulin release in both HIT-T15 cells and rodent islets. In both cases, loss of GPR119 rendered AR231453 inactive. AR231453 also enhanced glucose-dependent insulin release in vivo and improved oral glucose tolerance in wild-type mice but not in GPR119-deficient mice. Diabetic KK/A(y) mice were also highly responsive to AR231453. Orally active GPR119 agonists may offer significant promise as novel antihyperglycemic agents acting in a glucose-dependent fashion.