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

描述（由申请人提供）：肥胖和2型糖尿病（T2DM）是世界性的流行病，从肥胖到异常葡萄糖稳态的机制尚不清楚。越来越多的证据表明，下丘脑内感知周围营养物质和激素以调节食物摄入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2型糖尿病联系起来的可能性。胰高血糖素样肽-1 （Glucagon-like peptide-1, GLP-1）由肠道分泌，是胰岛素分泌的有力刺激物，对正常的葡萄糖稳态至关重要。几种长效GLP-1类似物最近被开发用于治疗2型糖尿病。这些新的基于GLP-1的药物被认为直接作用于胰腺细胞以促进胰岛素的释放。然而，GLP-1也在大脑中产生，在几个关键区域的受体参与控制食物摄入和葡萄糖稳态。我们的初步数据表明，下丘脑内的GLP-1信号调节外周葡萄糖水平，中枢神经系统GLP-1调节葡萄糖水平和食物摄入的能力取决于葡萄糖的可用性。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，这是稳态调节的关键控制因素。葡萄糖激酶（GK）被认为具有葡萄糖传感器的功能，我们提出中枢GLP-1调节能量和葡萄糖稳态的能力取决于葡萄糖的可用性，而葡萄糖的可用性反过来又通过GK进行调节。具体来说，本提案的目标是确定中枢神经系统中哪些GLP-1r群体与GK功能和葡萄糖感知有关，从而调节食物摄入和葡萄糖稳态。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元机制。

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.