Study of protective effects and transcriptional regulation by a novel fatty acid receptor in pancreatic beta cells: its implication in lipotoxicity and glucose intolerance

为了探讨GPR40在瘦素缺乏症中的意义，我们在本实验室建立的遗传性肥胖瘦素缺乏症大鼠（Lepmkyo/mkyo）胰岛中评估了GPR40 mRNA的表达。Lepmkyo/mkyo的体重呈年龄依赖性增加。随着肥胖的进展，高甘油三酯血症和葡萄糖不耐受症同时恶化。52周龄后，Lepmkyo/mkyo体重下降，60周龄左右死亡。Lepmkyo/mkyo的肝脂质浓度和血转氨酶明显升高，提示Lepmkyo/mkyo的死亡与肝功能衰竭有关。Lepmkyo/mkyo组空腹胰岛素水平明显升高，β细胞面积明显增加。相比之下，葡萄糖负荷后的早期胰岛素反应明显降低。GPR40 mRNA水平在Lepmkyo/mkyo的胰岛中降低，提示GPR40可能参与瘦素缺乏型肥胖相关葡萄糖不耐受的胰岛素分泌。

To explore the significance of GPR40 in leptin deficiency, GPR40 mRNA expression was assessed in pancreatic islets of genetically obese leptin-deficient rats (Lepmkyo/mkyo), which were established by our laboratory. Body weight of Lepmkyo/mkyowas increased an age-dependent manner. Hypertriglyceridimia and glucose intorelance were worsened in parralell with the progression of obesity. After the age of ~52 weeks, body weight of Lepmkyo/mkyowas decreased and they dead around the age of 60 weeks. Liver lipid concentration and blood transaminase were markedly increased in Lepmkyo/mkyo, suggesting involvement of liver failure in the death of Lepmkyo/mkyo. Fasting insulin levels were markedly increased in Lepmkyo/mkyo, and beta cell area was markedly increased. In contrast, early insulin response after glucose load was markedly decreased. GPR40 mRNA levels were decreased in pancreatic islets of Lepmkyo/mkyo, suggesting possible involvement of GPR40 in insulin secretion in leptin deficient obesity-associated glucose intolerance.