Glucose-Sensing by Neurons: Its Importance and the Role of UCP2

神经元的葡萄糖感受：其重要性和UCP 2的作用 大脑对葡萄糖的感知是一种有据可查的现象，具有潜在的重要意义， 2型糖尿病的发病机制。之前的电生理研究已经确定亚群 神经元的生长受到葡萄糖的调节。当葡萄糖升高时，“葡萄糖兴奋”的神经元会去兴奋并增加 他们的射击率。葡萄糖兴奋神经元的实例包括弓状核中的POMC神经元，MCH 外侧下丘脑中的神经元和腹内侧下丘脑（VMH）中的神经元亚组。 负责葡萄糖激发的分子装置被认为与在 胰腺（3-细胞）。具体地说，神经元氧化葡萄糖和/或乳酸（后者由葡萄糖产生 在神经胶质细胞中的代谢），增加ATP/ADP比率。然后关闭神经元KATP通道， 使神经元去极化，然后增加其放电率。虽然“P细胞样”葡萄糖现象- 大脑中的感知是稳健的，其生理相关性及其对疾病状态（例如2型糖尿病）的贡献 糖尿病是未知的。这些研究的总体目标是评估“P细胞样”葡萄糖敏感的作用。 在正常生理和2型糖尿病的发展过程中，这将是完成 通过使用基因工程小鼠。首先，我们将破坏“P-细胞样”葡萄糖感应， 神经元特异性的方式，通过突变KATP通道的转基因表达，然后确定这是否 不利地影响胰岛素/葡萄糖稳态（目的1）。其次，我们将确定解偶联蛋白-2是否 （UCP 2）负调节神经元中的“P细胞样”葡萄糖敏感，以及这是否可能是导致 2型糖尿病的葡萄糖敏感缺陷（Aim 2）。第三，我们将确定是否存在UCP 2， 神经元，我们预测这将防止葡萄糖感知的损失，改善肥胖引起的损伤， 胰岛素/葡萄糖稳态（目的3）。 这项应用中提出的研究可以为大脑在发病机制中的作用提供新的见解 2型糖尿病这种见解可能会导致这种疾病的新疗法。

Glucose-Sensing by Neurons: its Importance and the Role of UCP2 Glucose-sensing by the brain is a well documented phenomenon with potentially important implications for the pathogenesis of type 2 diabetes. Prior electrophysiological studies have determined that subpopulations of neurons are regulated by glucose. As glucose rises, "glucose-excited" neurons depolarize and increase their firing rate. Examples of glucose-excited neurons include POMC neurons in the arcuate nucleus, MCH neurons in the lateral hypothalamus and a subgroup of neurons in the ventromedial hypothalamus (VMH). The molecular apparatus responsible for excitation by glucose is thought to have similarities to that found in pancreatic (3-cells. Specifically, neuronal oxidation of glucose and/or lactate (thelatter generated by glucose metabolism in glial cells), increases the ATP/ADP ratio. This then closes neuronal KATP channels, depolarizing the neuron which then increases its firing rate. While the phenomenon of "P-cell-like" glucose- sensing in the brain is robust, its physiologic relevance and its contribution to disease states such as type 2 diabetes, is unknown. The overall goal of these studies is to assess the role of "p-cell-like" glucose-sensing by neurons in normal physiology and in the development of type 2 diabetes. This will be accomplished through the use of genetically engineered mice. First, we will disrupt "P-cell-like" glucose-sensing in a neuron-specific fashion, through transgenic expression of a mutant KATP channel, and then determine if this adversely affects insulin / glucose homeostasis (Aim 1). Second, we will determine if uncoupling protein-2 (UCP2) negatively regulates "P-cell-like" glucose-sensing in neurons and whether this could be a cause of defective glucose-sensing in type 2 diabetes (Aim 2). Third, we will determine if absence of UCP2 in neurons, which we predict will prevent loss of glucose-sensing, improves obesity-induced impairments in insulin / glucose homeostasis (Aim 3). Studies proposed in this application could provide novel insight into the role of the brain in the pathogenesis of type 2 diabetes. Such insight could result in novel treatments for this disease.