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

神经元的葡萄糖感觉：其重要性和UCP2的作用 大脑对葡萄糖的感知是一种有充分证据的现象，它可能对 2型糖尿病的发病机制。先前的电生理学研究已经确定了亚群 的神经元是由葡萄糖调节的。当血糖升高时，“葡萄糖兴奋”的神经元去极化并增加。 他们的射击率。葡萄糖兴奋神经元的例子包括弓状核中的POMC神经元，MCH 下丘脑外侧的神经元和下丘脑腹内侧(VMH)的神经元亚群。 负责葡萄糖刺激的分子装置被认为与文献中发现的相似 胰腺(3-细胞。具体地说，葡萄糖和/或乳酸(由葡萄糖产生的乳酸)的神经元氧化 神经胶质细胞的代谢)，增加了ATP/ADP的比率。这就关闭了神经元的KATP通道， 使神经元去极化，从而提高其放电频率。而“P细胞样”葡萄糖的现象-- 大脑中的感觉是强大的，它的生理相关性及其对2型等疾病状态的贡献 糖尿病，是未知的。这些研究的总体目标是评估“类p细胞”葡萄糖感应的作用。 由神经元在正常生理和2型糖尿病的发展过程中发挥作用。这将会实现的 通过使用转基因小鼠。首先，我们将扰乱“P细胞样”的葡萄糖感应。 神经元特异性方式，通过转基因表达突变的KATP通道，然后确定这是否 对胰岛素/葡萄糖稳态产生不利影响(目标1)。第二，我们将确定解偶联蛋白-2 (UCP2)负性调节神经元中“P细胞样”的葡萄糖感觉，以及这是否可能是导致 2型糖尿病患者的葡萄糖感觉缺陷(目标2)。第三，我们将确定UCP2是否在 神经元，我们预测将防止葡萄糖感知的丧失，改善肥胖诱导的损伤 胰岛素/葡萄糖稳态(目标3)。 这项申请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型糖尿病患者。这种洞察力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.