Steneberg Pär, Rubins Nir, Bartoov-Shifman Reut, Walker Michael D, Edlund Helena
Umeå Center for Molecular Medicine, University of Umeå, SE-901 87 Umeå, Sweden.
Cell Metab. 2005 Apr;1(4):245-58. doi: 10.1016/j.cmet.2005.03.007.
Obesity is typically associated with elevated levels of free fatty acids (FFAs) and is linked to glucose intolerance and type 2 diabetes. FFAs exert divergent effects on insulin secretion from beta cells: acute exposure to FFAs stimulates insulin secretion, whereas chronic exposure impairs insulin secretion. The G protein-coupled receptor GPR40 is selectively expressed in beta cells and is activated by FFAs. We show here that GPR40 mediates both acute and chronic effects of FFAs on insulin secretion and that GPR40 signaling is linked to impaired glucose homeostasis. GPR40-deficient beta cells secrete less insulin in response to FFAs, and loss of GPR40 protects mice from obesity-induced hyperinsulinemia, hepatic steatosis, hypertriglyceridemia, increased hepatic glucose output, hyperglycemia, and glucose intolerance. Conversely, overexpression of GPR40 in beta cells of mice leads to impaired beta cell function, hypoinsulinemia, and diabetes. These results suggest that GPR40 plays an important role in the chain of events linking obesity and type 2 diabetes.
肥胖通常与游离脂肪酸（FFAs）水平升高相关，并且与葡萄糖耐受不良和2型糖尿病有关。游离脂肪酸对β细胞的胰岛素分泌产生不同的影响：急性暴露于游离脂肪酸会刺激胰岛素分泌，而长期暴露则会损害胰岛素分泌。G蛋白偶联受体GPR40在β细胞中选择性表达，并被游离脂肪酸激活。我们在此表明，GPR40介导游离脂肪酸对胰岛素分泌的急性和慢性影响，并且GPR40信号传导与葡萄糖稳态受损有关。缺乏GPR40的β细胞对游离脂肪酸的反应分泌较少的胰岛素，GPR40的缺失保护小鼠免受肥胖诱导的高胰岛素血症、肝脂肪变性、高甘油三酯血症、肝葡萄糖输出增加、高血糖和葡萄糖耐受不良的影响。相反，在小鼠β细胞中过表达GPR40会导致β细胞功能受损、低胰岛素血症和糖尿病。这些结果表明，GPR40在连接肥胖和2型糖尿病的一系列事件中起重要作用。
