β-Cell Glucagon-Like Peptide-1 Receptor Contributes to Improved Glucose Tolerance After Vertical Sleeve Gastrectomy
β-Cell Glucagon-Like Peptide-1 Receptor Contributes to Improved Glucose Tolerance After Vertical Sleeve Gastrectomy
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DOI：
10.1210/en.2016-1302
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发表时间：
2016-09-01
期刊：
影响因子：
4.8
通讯作者：
Cummings, Bethany P.
中科院分区：
文献类型：
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作者：
Garibay, Darline;McGavigan, Anne K.;Cummings, Bethany P.
垂直袖状胃切除术(VSG)可产生较高的2型糖尿病缓解率；然而，导致这种情况的机制仍不完全清楚。胰高血糖素样肽-1(GLP-1)是一种有助于维持血糖稳态的胃肠激素，在VSG后升高。VSG诱导的餐后GLP-1分泌增加被认为有助于VSG的血糖调节益处；然而，以前的工作一直是模棱两可的。为了测试增强的β细胞GLP-1受体(GLP-1R)信号的作用，我们使用了β细胞特异性的他莫昔芬诱导的GLP-1R基因敲除小鼠模型。雄性β细胞特异性GLP-1R(β细胞+/+)野生型(WT)和GLP-1R(β细胞+/+)基因敲除(KO)窝仔被置于高脂饲料中6周，然后在剩下的研究中切换到添加他莫昔芬的高脂肪饲料中。小鼠在他莫昔芬饮食2周后接受假手术或VSG手术，并在术后随意喂养。小鼠于术后3周接受口服葡萄糖耐量试验，术后6周处死。VSG降低体重和食物摄入量，与基因无关。然而，与假手术组相比，VSG组大鼠的糖耐量仅有改善，而VSG KO组大鼠的糖耐量较VSG组有所降低。在口服葡萄糖耐量试验中，VSG KO组与VSG WT组相比，葡萄糖刺激的胰岛素分泌增加是钝化的。因此，我们的数据表明，增强的β细胞GLP-1R信号有助于通过促进葡萄糖刺激的胰岛素分泌增加来改善VSG后的血糖调节。
Vertical sleeve gastrectomy (VSG) produces high rates of type 2 diabetes remission; however, the mechanisms responsible for this remain incompletely defined. Glucagon-like peptide-1 (GLP-1) is a gut hormone that contributes to the maintenance of glucose homeostasis and is elevated after VSG. VSG-induced increases in postprandial GLP-1 secretion have been proposed to contribute to the glucoregulatory benefits of VSG; however, previous work has been equivocal. In order to test the contribution of enhanced beta-cell GLP-1 receptor (GLP-1R) signaling we used a beta-cell-specific tamoxifen-inducible GLP-1R knockout mouse model. Male beta-cell-specific Glp-1r(beta-cell+/+) wild type (WT) and Glp-1r(beta-cell+/+) knockout (KO) littermates were placed on a high-fat diet for 6 weeks and then switched to high-fat diet supplemented with tamoxifen for the rest of the study. Mice underwent sham or VSG surgery after 2 weeks of tamoxifen diet and were fed ad libitum postoperatively. Mice underwent oral glucose tolerance testing at 3 weeks and were euthanized at 6 weeks after surgery. VSG reduced body weight and food intake independent of genotype. However, glucose tolerance was only improved in VSG WT compared with sham WT, whereas VSG KO had impaired glucose tolerance relative to VSG WT. Augmentation of glucose-stimulated insulin secretion during the oral glucose tolerance test was blunted in VSG KO compared with VSG WT. Therefore, our data suggest that enhanced beta-cell GLP-1R signaling contributes to improved glucose regulation after VSG by promoting increased glucose-stimulated insulin secretion.