Tremblay Frédéric, Richard Ann-Marie T, Will Sarah, Syed Jameel, Stedman Nancy, Perreault Mylène, Gimeno Ruth E
Department of Metabolic Diseases,Wyeth Research, Cambridge, Massachusetts 02140, USA.
Endocrinology. 2009 Jun;150(6):2586-95. doi: 10.1210/en.2008-1251. Epub 2009 Feb 12.
GPR39 is a G protein-coupled receptor expressed in liver, gastrointestinal tract, adipose tissue, and pancreas. We have recently shown that young GPR39(-/-) mice have normal body weight, food intake, and fasting glucose and insulin levels. In this study, we examined the role of GPR39 in aging and diet-induced obese mice. Body weight and food intake were similar in wild-type and GPR39(-/-) mice as they aged from 12 to 52 wk or when fed a low-fat/high-sucrose or high-fat/high-sucrose diet. Fifty-two-week-old GPR39(-/-) mice showed a trend toward decreased insulin levels after oral glucose challenge. When fed either a low-fat/high-sucrose or high-fat/high-sucrose diet, GPR39(-/-) mice had increased fed glucose levels and showed decreased serum insulin levels during an oral glucose tolerance test in the face of unchanged insulin tolerance. Pancreas morphology and glucose-stimulated insulin secretion in isolated islets from wild-type and GPR39(-/-) mice were comparable, suggesting that GPR39 is not required for pancreas development or ex vivo insulin secretion. Small interfering RNA-mediated knockdown of GPR39 in clonal NIT-1 beta-cells revealed that GPR39 regulates the expression of insulin receptor substrate-2 and pancreatic and duodenal homeobox-1 in a cell-autonomous manner; insulin receptor substrate-2 mRNA was also significantly decreased in the pancreas of GPR39(-/-) mice. Taken together, our data indicate that GPR39 is required for the increased insulin secretion in vivo under conditions of increased demand, i.e. on development of age-dependent and diet-induced insulin resistance. Thus, GPR39 agonists may have potential for the treatment of type 2 diabetes.
GPR39是一种G蛋白偶联受体，在肝脏、胃肠道、脂肪组织和胰腺中表达。我们最近发现，年轻的GPR39基因敲除小鼠体重、食物摄入量以及空腹血糖和胰岛素水平均正常。在本研究中，我们检测了GPR39在衰老和饮食诱导肥胖小鼠中的作用。野生型和GPR39基因敲除小鼠在12至52周龄期间，或喂食低脂/高蔗糖或高脂/高蔗糖饮食时，体重和食物摄入量相似。52周龄的GPR39基因敲除小鼠口服葡萄糖激发后胰岛素水平有下降趋势。喂食低脂/高蔗糖或高脂/高蔗糖饮食时，GPR39基因敲除小鼠在口服葡萄糖耐量试验中进食后血糖水平升高，血清胰岛素水平降低，而胰岛素耐受性未改变。野生型和GPR39基因敲除小鼠分离胰岛的胰腺形态和葡萄糖刺激的胰岛素分泌相当，提示胰腺发育或体外胰岛素分泌不需要GPR39。在克隆的NIT-1β细胞中，小干扰RNA介导的GPR39基因敲低显示，GPR39以细胞自主方式调节胰岛素受体底物-2和胰腺十二指肠同源盒-1的表达；GPR39基因敲除小鼠胰腺中胰岛素受体底物-2 mRNA也显著降低。综上所述，我们的数据表明，在需求增加的情况下，即在年龄依赖性和饮食诱导的胰岛素抵抗发展时，体内胰岛素分泌增加需要GPR39。因此，GPR39激动剂可能具有治疗2型糖尿病的潜力。
