Montréal Diabetes Research Center, Research Centre of the Montréal University Hospital, University of Montréal, Montréal, QC, Canada.
Diabetes. 2009 Nov;58(11):2607-15. doi: 10.2337/db09-0362. Epub 2009 Aug 31.
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 approximately 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.
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，但它在体内胰岛素分泌中的作用及其作用机制仍不确定。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内的细胞内燃料代谢。
通过高血糖钳夹和高胰岛素正常血糖钳夹分别评估 GPR40 敲除小鼠及其野生型同窝仔鼠的胰岛素分泌和敏感性。采用转录组分析、代谢研究和脂质谱分析来确定 GPR40 是否调节胰岛内的细胞内燃料代谢。
GPR40 敲除的空腹和进食小鼠的体内葡萄糖和精氨酸刺激的胰岛素分泌分别降低了约 60%，而胰岛素敏感性没有变化。GPR40 缺失既不影响分离胰岛的基因表达谱，也不影响葡萄糖和棕榈酸的细胞内代谢。分离胰岛的脂质谱分析表明，体外棕榈酸引起的甘油三酯增加和溶血磷脂乙醇胺减少在野生型和敲除型胰岛中相似。相比之下，在体外脂肪酸刺激下，野生型胰岛中观察到的细胞内肌醇磷酸盐水平增加在敲除型胰岛中不存在。
这些结果表明，GPR40 的缺失不仅损害了体内对脂肪酸的胰岛素分泌，也损害了对葡萄糖和精氨酸的胰岛素分泌，而不改变胰岛内的细胞内燃料代谢，其机制可能涉及 GPR40 激活下游肌醇磷酸盐的产生。
