A G protein-coupled receptor for fatty acids, GPR40 : a novel therapeutic target in treatment of adipotoxicity and glucose intolerance

为了阐明GPR 40在糖尿病中的调节和病理生理学意义，我们研究了Koletsky大鼠（fa^k/fa^k）胰岛中GPR 40基因的表达，并与瘦的同窝出生大鼠（+/+）进行了比较。在14周龄的建立了葡萄糖耐受不良的fa^k/fa^k中，胰岛中的GPR 40基因表达显著降低（~1/3）。在来自fa^k/fa^k的分离胰岛中，油酸引起的胰岛素分泌增加明显减弱。在fa^k/fa^k的胰岛中，组织甘油三酯水平增加~3倍。值得注意的是，在fa^k/fa^k的胰岛中，Pdx 1的mRNA表达显著降低（~1/2），据报道，Pdx 1的推定结合结构域位于GPR 40启动子中。我们的研究结果表明，GPR 40表达下降和胰岛素分泌失调的胰腺β细胞与脂质积累之间的联系，其中Pdx 1基因表达下降可能在GPR 40表达的调节中发挥关键作用。这些数据还为Koletsky大鼠作为研究胰腺β细胞中脂质积聚和功能障碍的合适模型提供了证据。

To elucidate the regulation and pathophysiological implication of GPR40 in diabetes, we investigated GPR40 gene expression in pancreatic islets in Koletsky rats (fa^k/fa^k), a genetically obese model with a homozygous nonsense mutation in the ObR gene, as reported by us, and compared with lean littermates (+/+). In 14-week-old fa^k/fa^k with established glucose intolerance, GPR40 gene expression in pancreatic islets markedly (~1/3) decreased. Augmentation of insulin secretion in response to oleic acids was markedly attenuated in isolated islets from fa^k/fa^k. Tissue triglyceride levels were ~3-folds increased in pancreatic islets of fa^k/fa^k. Notably, mRNA expression of Pdx1, for which a putative binding domain is reported in the GPR40 promoter, was markedly (~1/2) decreased in pancreatic islets of fa^k/fa^k. Our results suggest a link between decreased GPR40 expression and dysregulated insulin secretion in pancreatic beta cells with lipid accumulation, where decreased Pdx1 gene expression may play a pivotal role in the regulation of GPR40 expression. The data also provide evidence for Koletsky rats as a suitable model for investigation of lipid accumulation and dysfunction in pancreatic beta cells.