Deletion of GPR40 impairs glucose-induced insulin secretion in vivo in mice without affecting intracellular fuel metabolism in islets.
Deletion of GPR40 impairs glucose-induced insulin secretion in vivo in mice without affecting intracellular fuel metabolism in islets.
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作者：
Alquier T;Peyot ML;Latour MG;Kebede M;Sorensen CM;Gesta S;Ronald Kahn C;Smith RD;Jetton TL;Metz TO;Prentki M;Poitout V
g蛋白偶联受体GPR40介导脂肪酸增强葡萄糖刺激的胰岛素分泌，但其在体内对胰岛素分泌的贡献及其作用机制尚不清楚。本研究旨在确定GPR40是否在体内控制胰岛素分泌并调节胰岛细胞内燃料代谢。分别用高血糖钳和高胰岛素钳评估GPR40基因敲除小鼠及其野生型幼崽的胰岛素分泌和敏感性。转录组学分析、代谢研究和脂质分析被用来确定GPR40是否调节胰岛细胞内燃料代谢。在GPR40基因敲除的禁食和喂养小鼠中，葡萄糖和精氨酸刺激的体内胰岛素分泌减少了约60%，而胰岛素敏感性没有变化。GPR40缺失既不影响基因表达谱，也不影响离体胰岛细胞内葡萄糖和棕榈酸盐代谢。离体胰岛的脂质分析显示，在野生型和敲除型胰岛中，甘油三酯的增加和溶磷脂酰乙醇胺种类的减少对棕榈酸盐的反应是相似的。相比之下，在野生型胰岛中观察到的细胞内肌醇磷酸盐水平对脂肪酸的体外反应在敲除胰岛中不存在。这些结果表明，GPR40的缺失不仅会损害体内对脂肪酸的胰岛素分泌，还会损害葡萄糖和精氨酸的胰岛素分泌，而不会改变胰岛细胞内的燃料代谢，其机制可能涉及GPR40激活下游肌醇磷酸的产生。
The G-protein–coupled receptor GPR40 mediates fatty acid potentiation of glucose-stimulated insulin secretion, but its contribution to insulin secretion in vivo and mechanisms of action remain uncertain. This study was aimed to ascertain whether GPR40 controls insulin secretion in vivo and modulates intracellular fuel metabolism in islets. Insulin secretion and sensitivity were assessed in GPR40 knockout mice and their wild-type littermates by hyperglycemic clamps and hyperinsulinemic euglycemic clamps, respectively. Transcriptomic analysis, metabolic studies, and lipid profiling were used to ascertain whether GPR40 modulates intracellular fuel metabolism in islets. Both glucose- and arginine-stimulated insulin secretion in vivo were decreased by ∼60% in GPR40 knockout fasted and fed mice, without changes in insulin sensitivity. Neither gene expression profiles nor intracellular metabolism of glucose and palmitate in isolated islets were affected by GPR40 deletion. Lipid profiling of isolated islets revealed that the increase in triglyceride and decrease in lyso-phosphatidylethanolamine species in response to palmitate in vitro was similar in wild-type and knockout islets. In contrast, the increase in intracellular inositol phosphate levels observed in wild-type islets in response to fatty acids in vitro was absent in knockout islets. These results indicate that deletion of GPR40 impairs insulin secretion in vivo not only in response to fatty acids but also to glucose and arginine, without altering intracellular fuel metabolism in islets, via a mechanism that may involve the generation of inositol phosphates downstream of GPR40 activation.
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影响因子：
3.5
作者：
Ma, Dexuan;Lu, Li;Yamashima, Tetsurnori
通讯作者：
Yamashima, Tetsurnori
DOI：
10.1152/ajpendo.00035.2005
发表时间：
2005-10-01
影响因子：
5.1
作者：
Fujiwara, K;Maekawa, F;Yada, T
通讯作者：
Yada, T
影响因子：
4.8
作者：
Chu, Zhi-Liang;Jones, Robert M.;Leonard, James
通讯作者：
Leonard, James
影响因子：
4
作者：
Massa, ML;Borelli, MI;Gagliardino, JJ
通讯作者：
Gagliardino, JJ
影响因子：
7.7
作者：
Edfalk S;Steneberg P;Edlund H
通讯作者：
Edlund H