Role of Glucokinase in GLP-1 Regulation of Energy and Glucose Homeostasis

描述(申请人提供)：肥胖和2型糖尿病(T2 DM)是世界性的流行病，从肥胖到血糖稳态异常的机制仍然难以捉摸。越来越多的证据表明，下丘脑中感知外周营养物质和激素以调节食物摄入量的神经元也调节葡萄糖稳态。这增加了中枢神经系统机制可能将肥胖和T2 DM联系起来的可能性。胰高血糖素样肽-1(GLP-1)由肠道分泌，对胰岛素的分泌有很强的刺激作用，是维持正常血糖稳态所必需的。几个长效的GLP-1类似物最近被开发出来用于治疗T2 DM。这些新的基于GLP-1的药物被认为直接作用于胰腺β细胞，促进胰岛素的释放。然而，GLP-1也是在大脑中产生的，几个关键区域的受体与控制食物摄入量和葡萄糖稳态有关。我们的初步数据表明，下丘脑中的GLP-1信号调节外周血糖水平，并且CNS GLP-1调节血糖水平和食物摄入量的能力依赖于葡萄糖的供应。在β细胞中，GLP-1诱导胰岛素分泌的能力依赖于环境葡萄糖浓度的升高，而葡萄糖浓度是体内平衡调节的关键控制因素。葡萄糖激酶(GK)被认为是一种葡萄糖感受器，我们认为中心GLP-1调节能量和葡萄糖动态平衡的能力依赖于葡萄糖的可获得性，而这反过来又是通过GK来调节的。具体地说，这项建议的目标是确定中枢神经系统中哪些GLP-1R群体与GK功能和葡萄糖感知在调节食物摄入量和葡萄糖动态平衡方面有关。这项建议的长期目标是阐明肥胖与2型糖尿病之间的特定细胞和神经机制。

DESCRIPTION (provided by applicant): Obesity and type 2 diabetes mellitus (T2DM) are worldwide epidemics and the mechanisms that lead from obesity to abnormal glucose homeostasis remain elusive. Accumulating evidence suggests that the neurons within the hypothalamus that sense peripheral nutrients and hormones to regulate food intake also regulate glucose homeostasis. This raises the possibility that CNS mechanisms could link obesity and T2DM. Glucagon-like peptide-1 (GLP-1), secreted by the intestine, is a potent stimulus for insulin secretion and is essential for normal glucose homeostasis. Several long-acting GLP-1 analogs have recently been developed for the treatment of T2DM. These new GLP-1 based drugs are presumed to work directly on the pancreatic beta- cell to promote insulin release. However, GLP-1 is also made in the brain, with receptors in several key regions implicated in the control of food intake and glucose homeostasis. Our preliminary data indicate that GLP-1 signaling within the hypothalamus regulates peripheral glucose levels and that the ability of CNS GLP-1 to regulate both glucose levels and food intake is dependent on glucose availability. In the beta-cell, the ability of GLP-1 to induce insulin secretion is dependent on elevated ambient glucose concentrations, a key control for homeostatic regulation. Glucokinase (GK) has been proposed to function as a glucose sensor, and we propose that the ability of central GLP-1 to regulate energy and glucose homeostasis is dependent upon glucose availability and that this in turn is regulated via GK. Specifically, the goals of this proposal are to determine which populations of GLP-1r within the CNS are linked to GK function and glucose sensing in regulation of both food intake and glucose homeostasis. The long term goals of this proposal are to elucidate specific cellular and neuronal mechanisms that link obesity to type 2 diabetes mellitus.