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（T2 DM）是全球流行病，导致肥胖和葡萄糖稳态异常的机制仍然难以捉摸。越来越多的证据表明，下丘脑内的神经元感知外周营养和激素来调节食物摄入，也调节葡萄糖的稳态。这增加了CNS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，是胰岛素分泌的有效刺激物，对正常葡萄糖稳态至关重要。最近开发了几种长效GLP-1类似物用于治疗T2 DM。这些基于GLP-1的新药被认为直接作用于胰腺β细胞以促进胰岛素释放。然而，GLP-1也在大脑中产生，在几个关键区域中有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，CNS 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取决于升高的环境葡萄糖浓度，这是稳态调节的关键控制。葡萄糖激酶（GK）已被提出作为葡萄糖传感器的功能，我们提出，中央GLP-1的能力，以调节能量和葡萄糖稳态是依赖于葡萄糖的可用性，这反过来又通过GK调节。具体而言，本提案的目的是确定CNS内哪些GLP-1 r群体与GK功能和葡萄糖感知相关，以调节摄食量和葡萄糖稳态。该提案的长期目标是阐明将肥胖与2型糖尿病联系起来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.