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

胰腺β细胞中新型脂肪酸受体的保护作用和转录调节研究：其在脂毒性和葡萄糖耐受不良中的意义

• 批准号: 23791029
• 负责人: TOMITA Tsutomu
• 金额: $ 2.66万
• 依托单位: Kyoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23791029/
• 关键词: GPR40; 脂肪毒性; 糖尿病; 耐糖能異常; レプチン; 遊離脂肪酸; インスリン分泌; 膵島機能調節; 糖尿病治療薬; 創薬標的

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.

为了探讨GPR 40在瘦素缺乏中的意义，我们检测了本实验室建立的遗传性肥胖瘦素缺乏大鼠（Lepmkyo/mkyo）胰岛中GPR 40 mRNA的表达。Lepmkyo/mkyo的体重随年龄增长而增加。随着肥胖程度的加重，高脂血症和血糖异常加重。Lepmkyo/mkyo在~52周龄后体重下降，60周龄左右死亡。Lepmkyo/mkyo的肝脏脂质浓度和血液转氨酶显著升高，表明Lepmkyo/mkyo的死亡与肝功能衰竭有关。Lepmkyo/mkyo组空腹胰岛素水平显著升高，β细胞面积显著增加。相反，葡萄糖负荷后的早期胰岛素反应明显降低。GPR 40 mRNA水平在Lepmkyo/mkyo的胰岛中降低，表明GPR 40可能参与瘦素缺乏性肥胖相关的葡萄糖耐受不良的胰岛素分泌。

项目成果

新規のG蛋白共役型-脂質受容体群GPR40、GP119の臨床的意義

新型G蛋白偶联脂质受体GPR40和GP119的临床意义

• 发表时间: 2012
• 作者: 冨田努;他.
• 通讯作者: 他.

Clinical Implications of G Protein-Coupled Lipid Receptors, GPR40 and GPR119,9thInternational Diabetes Federation Western Pacific Region Congress

G蛋白偶联脂质受体、GPR40和GPR119的临床意义，第九届国际糖尿病联盟西太平洋地区大会

• 发表时间: 2012
• 作者: T. Tomita;他
• 通讯作者: 他

膵β細胞に高発現し、中・長鎖脂肪酸をリガンドするG蛋白共役型受容体GPR40の遺伝性肥満モデルの膵島での発現調節

GPR40（一种在胰腺β细胞和配体中链和长链脂肪酸中高表达的G蛋白偶联受体）在遗传性肥胖模型胰岛中表达的调节

• 发表时间: 2011
• 作者: 冨田努;細田公則;小鳥真司;孫徹;藤倉純二;岩倉浩;野口倫生;森栄作;内藤雅喜;吉良友里;日下部徹;海老原健;益崎裕章;中尾一和
• 通讯作者: 中尾一和

G蛋白共役型-脂肪酸受容体GPR40の遺伝性肥満モデルの膵島での発現調節

遗传性肥胖模型胰岛中 G 蛋白偶联脂肪酸受体 GPR40 表达的调节

• 发表时间: 2011
• 作者: 冨田努;細田公則;小鳥真司;孫 徹;藤倉純二;岩倉浩;野口倫生;日下部徹;海老原健;中尾一和
• 通讯作者: 中尾一和