The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse
The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse
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DOI：
10.1016/j.cmet.2005.03.007
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发表时间：
2005-04-01
期刊：
影响因子：
29
通讯作者：
Edlund, H
中科院分区：
文献类型：
--
作者：
Steneberg, R;Rubins, N;Edlund, H
肥胖通常与游离脂肪酸（FFA）水平升高有关，并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刺激胰岛素分泌，而慢性暴露损害胰岛素分泌。G蛋白偶联受体GPR40在P细胞中选择性表达，并被FFA激活。我们发现GPR40介导FFA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。GPR40缺陷的β细胞响应于FFA分泌较少的胰岛素，并且GPR40的缺失保护小鼠免于肥胖诱导的高胰岛素血症、肝脂肪变性、高胰岛素血症、增加的肝葡萄糖输出、高血糖症和葡萄糖耐受不良。相反，小鼠β细胞中GPR40的过表达导致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型糖尿病的事件链中起着重要作用。
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 P 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.