Novel Role for CNS GLP in Glucose Homeostasis

描述（由申请人提供）： 肥胖和2型糖尿病是国家和世界范围的流行病。从肥胖到异常葡萄糖稳态和最终2型糖尿病的生理机制仍然难以捉摸。有趣的是，越来越多的证据表明，下丘脑内的神经元对外周营养素和激素（如胰岛素和瘦素）敏感，以调节外周葡萄糖稳态。这些数据表明大脑是肥胖和2型糖尿病之间的重要联系。 大量证据表明胰高血糖素样肽-1（GLP-1）在控制血液中葡萄糖水平方面具有重要作用，这导致最近批准长效GLP-1类似物用于治疗2型糖尿病。GLP-1在肠道中产生，传统模型假设它作用于外周受体以增加胰岛素分泌。然而，GLP-1也是在大脑中产生的，GLP-1受体存在于大脑的几个关键区域，这些区域与外周葡萄糖水平的控制有关。事实上，桑多瓦尔博士进行的初步数据表明，GLP-1是一种调节外周葡萄糖水平的中枢神经系统信号。因此，本提案旨在了解脑GLP-1系统与外周葡萄糖稳态之间的联系机制。具体而言，本提案的目标是：确定哪些神经元GLP-1受体群介导GLP-1对外周葡萄糖水平的影响;葡萄糖水平变化在多大程度上是由于中枢GLP-1对肝脏或胰腺的影响;以及中枢GLP-1对外周葡萄糖水平作用的关键细胞内介质。最后，我们还将确定由饮食诱导的肥胖产生的葡萄糖损伤是否与中枢神经系统GLP-1功能损伤相关。这项研究的长期目标是阐明肥胖和2型糖尿病之间的特定细胞和神经机制。此外，目前的提案将为桑多瓦尔博士提供一个理想的机会，在她已经发展良好的人类研究专业知识基础上增加一些基本的研究技能。这将使她能够从事独立资助的假设驱动的转化研究职业，以阐明病因并为肥胖和2型糖尿病制定更好的治疗策略。

DESCRIPTION (provided by applicant): Obesity and type 2 diabetes mellitus are national and worldwide epidemics. The physiological mechanisms that lead from obesity to abnormal glucose homeostasis and eventual type 2 diabetes mellitus remain elusive. Interestingly, accumulating evidence suggests that neurons within the hypothalamus are sensitive to peripheral nutrients and hormones such as insulin and leptin to regulate peripheral glucose homeostasis. These data point to the brain as an important link between obesity and type 2 diabetes mellitus. A wide range of evidence points to an important role for glucagon-like peptide-1 (GLP-1) in the control of glucose levels in the blood and this has resulted in the recent approval of long-acting GLP-1 analogs for the treatment of type 2 diabetes mellitus. GLP-1 is made in the intestine and the conventional model hypothesizes that it acts on peripheral receptors to increase insulin secretion. However, GLP-1 is also made in the brain and GLP-1 receptors are found in several key regions of the brain that have been linked to the control of peripheral glucose levels. In fact, preliminary data conducted by Dr. Sandoval suggest that GLP-1, is a central nervous system signal that regulates peripheral glucose levels. Therefore, this proposal is aimed at understanding the mechanisms that link the brain GLP-1 system to peripheral glucose homeostasis. Specifically, the goals of this proposal are: to determine which populations of neuronal GLP-1 receptors mediate the effect of GLP-1 on peripheral glucose levels; the degree to which changing glucose levels are due to central GLP-1 effects on the liver or pancreas; and the key intracellular mediators of central GLP-1's action on peripheral glucose levels. Finally, we will also determine whether the glucose impairments produced by diet-induced obesity are associated with impairments of central nervous system GLP-1 function. The long-term goals of this research are to elucidate the specific cellular and neuronal mechanisms that link obesity and type 2 diabetes mellitus. Further, the current proposal will provide Dr. Sandoval an ideal opportunity to add a number of basic research skills to her already well-developed human research expertise. This will allow her to pursue an independently funded career of hypothesis-driven translational research to elucidate the etiology and develop better treatment strategies for obesity and type 2 diabetes mellitus.