The Glucagon-Like Peptide-1 Receptor Agonist Oxyntomodulin Enhances β-Cell Function but Does Not Inhibit Gastric Emptying in Mice
The Glucagon-Like Peptide-1 Receptor Agonist Oxyntomodulin Enhances β-Cell Function but Does Not Inhibit Gastric Emptying in Mice
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DOI：
10.1210/en.2008-0336
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发表时间：
2008-11-01
期刊：
影响因子：
4.8
通讯作者：
Drucker, Daniel J.
中科院分区：
文献类型：
--
作者：
Maida, Adriano;Lovshin, Julie A.;Drucker, Daniel J.
胰高血糖素原基因产生多种多肽，这些多肽在能量摄入、肠道运动和营养处理中发挥不同的作用。胰升糖素样肽-1(GLP-1)是一种由30个氨基酸组成的多肽，通过控制胰岛素和胰升糖素的分泌，通过抑制胃排空和食物摄入来调节血糖的稳态。氧合酶调节蛋白(oxyntomodrin，OXM)是一种由37个氨基酸组成的多肽，也可与GLP-1受体(GLP-1R)和GLP-1R结合，但尚未发现单独的OXM受体。在这里，我们展示了OXM，像其他GLP-1R激动剂一样，在口服和ip葡萄糖后刺激cAMP的形成和降低血糖，这些作用需要功能性的GLP-1R。OXM还以葡萄糖和GLP-1R依赖的方式直接刺激小鼠胰岛和INS-1细胞分泌胰岛素。此外，OXM还能改善链脲佐菌素诱导的小鼠胰岛β细胞的高血糖，显著减少细胞凋亡率，并直接减少塔普西林处理的INS-1细胞的凋亡率。出乎意料的是，口服葡萄糖后，OXM，而不是GLP-1R激动剂exendin-4，增加了血浆胰岛素水平。此外，在有效降低血糖的剂量下，OXM对抑制胃排空没有影响，但减少了WT小鼠的食物摄入量。综上所述，这些发现表明，尽管GLP-1和OXM等结构不同的胰高血糖素原衍生多肽与GLP-1R结合，但OXM在体内模拟了GLP-1R激动剂的部分但不是全部作用。这些发现可能会对使用OXM作为长效GLP-1R激动剂治疗代谢紊乱的治疗努力有所启示。(内分泌学149：5670-5678,2008)
The proglucagon gene gives rise to multiple peptides that play diverse roles in the control of energy intake, gut motility, and nutrient disposal. Glucagon-like peptide-1 (GLP-1), a 30-amino-acid peptide regulates glucose homeostasis via control of insulin and glucagon secretion and by inhibition of gastric emptying and food intake. Oxyntomodulin (OXM) a 37-amino-acid peptide also derived from the proglucagon gene, binds to both the glucagon and GLP-1 receptor (GLP-1R); however, a separate OXM receptor has not yet been identified. Here we show that OXM, like other GLP-1R agonists, stimulates cAMP formation and lowers blood glucose after both oral and ip glucose administration, actions that require a functional GLP-1R. OXM also directly stimulates insulin secretion from murine islets and INS-1 cells in a glucose- and GLP-1R-dependent manner. Moreover, OXM ameliorates hyperglycemia and significantly reduces apoptosis in murine beta-cells after streptozotocin administration and directly reduces apoptosis in thapsigargin-treated INS-1 cells. Unexpectedly, OXM, but not the GLP-1R agonist exendin-4, increased plasma levels of insulin after oral glucose administration. Moreover, OXM administered at doses that potently lower blood glucose had no effect on inhibition of gastric emptying but reduced food intake in WT mice. Taken together, these findings illustrate that although structurally distinct proglucagon-derived peptides such as GLP-1 and OXM engage the GLP-1R, OXM mimics some but not all of the actions of GLP-1R agonists in vivo. These findings may have implications for therapeutic efforts using OXM as a long-acting GLP-1R agonist for the treatment of metabolic disorders. (Endocrinology 149: 5670-5678, 2008)