Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion
Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion
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DOI：
10.1210/en.2012-1164
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发表时间：
2012-09-01
期刊：
影响因子：
4.8
通讯作者：
Okajima, Fumikazu
中科院分区：
文献类型：
--
作者：
Nakakura, Takashi;Mogi, Chihiro;Okajima, Fumikazu
卵巢癌G蛋白偶联受体1（OGR 1）已被证明是质子的受体。在本研究中，我们的目的是了解OGR 1是否在胰岛素分泌中起作用，如果是，它的方式。为此，我们创建了OGR 1缺陷小鼠，并在体内和体外检查胰岛素分泌活性。OGR 1缺乏减少了葡萄糖诱导的胰岛素分泌，尽管它与体内葡萄糖耐受不良无关。胰岛素敏感性增加和血浆胰高血糖素水平降低可以部分解释异常的正常葡萄糖耐量。体外胰岛实验表明，葡萄糖刺激的胰岛素分泌依赖于细胞外pH值，并且对OGR 1敏感; OGR 1缺乏和G（q/11）蛋白的抑制显着抑制了pH 7.4至7.0（但不是8.0）的胰岛素分泌。KCl和甲苯磺丁脲诱导的胰岛素分泌也被显著抑制，而由几种胰岛素促分泌素，包括加压素，胰高血糖素样肽1受体激动剂，和毛喉素诱导的胰岛素分泌，没有被OGR 1缺乏抑制。胰岛素分泌的抑制与葡萄糖诱导的细胞内Ca 2+浓度升高的减少有关。总之，OGR 1/G（q/11）蛋白途径被细胞外质子激活，细胞外质子存在于7.4的生理细胞外pH值下，并进一步被酸化刺激，导致胰岛素分泌增强，以响应高葡萄糖浓度和KCl。（内分泌学153：4171-4180，2012）
Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown as a receptor for protons. In the present study, we aimed to know whether OGR1 plays a role in insulin secretion and, if so, the manner in which it does. To this end, we created OGR1-deficient mice and examined insulin secretion activity in vivo and in vitro. OGR1 deficiency reduced insulin secretion induced by glucose administered ip, although it was not associated with glucose intolerance in vivo. Increased insulin sensitivity and reduced plasma glucagon level may explain, in part, the unusual normal glucose tolerance. In vitro islet experiments revealed that glucose-stimulated insulin secretion was dependent on extracellular pH and sensitive to OGR1; insulin secretion at pH 7.4 to 7.0, but not 8.0, was significantly suppressed by OGR1 deficiency and inhibition of G(q/11) proteins. Insulin secretion induced by KCl and tolbutamide was also significantly inhibited, whereas that induced by several insulin secretagogues, including vasopressin, a glucagon-like peptide 1 receptor agonist, and forskolin, was not suppressed by OGR1 deficiency. The inhibition of insulin secretion was associated with the reduction of glucose-induced increase in intracellular Ca2+ concentration. In conclusion, the OGR1/G(q/11) protein pathway is activated by extracellular protons existing under the physiological extracellular pH of 7.4 and further stimulated by acidification, resulting in the enhancement of insulin secretion in response to high glucose concentrations and KCl. (Endocrinology 153: 4171-4180, 2012)