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首页> 外文学位 >Role of hyperglycemia, hypoglycemia, and glucose transporter 4 on brain glucose sensing, counterregulation, and neuronal viability.
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Role of hyperglycemia, hypoglycemia, and glucose transporter 4 on brain glucose sensing, counterregulation, and neuronal viability.

机译：高血糖，低血糖和葡萄糖转运蛋白4在脑葡萄糖感应，反调节和神经元生存能力中的作用。

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摘要

As glucose is the main fuel source for the brain and a major nutrient for peripheral tissues, the brain must sense and respond to changes in blood glucose in order to sustain its own nutritional requirements and maintain whole body energy homeostasis. Disruption of brain glucose sensing results in impaired glucose tolerance, a hallmark in the pathogenesis of diabetes, as well as increased risk of severe hypoglycemia as occurs with insulin therapy. Thus, understanding how the brain senses and responds to changes in glucose is particularly important to individuals with diabetes. Experiments in this thesis investigated (1) the role of neuronal glucose transporter 4 (GLUT4) in glucose sensing and the counterregulatory response to hypoglycemia, (2) the adaptive response of the brain to antecedent hypoglycemia, and (3) the role of hyperglycemia and the hexosamine biosynthetic pathway (HBP) in the hypothalamus on regulating energy homeostasis. Neuronal GLUT4 was found to play a crucial role in modulating peripheral insulin sensitivity and was necessary for eliciting a full counterregulatory response to hypoglycemia. Antecedent moderate hypoglycemia preconditioned and protected the brain from neuronal injury and cognitive dysfunction induced by an episode of severe hypoglycemia. Finally, increased metabolism through the HBP in the hypothalamus decreased food intake and body weight and increased central and peripheral insulin sensitivity. These findings have important implications to individuals living with diabetes. Neuronal GLUT4 and the hypothalamic HBP both modulated whole body insulin sensitivity, and hence, both may be potential therapeutic targets to enhance insulin sensitivity, which would reduce the risk and improve management of diabetes. Further, patients on insulin therapy are at risk of experiencing hypoglycemia. Neuronal GLUT4 may be a therapeutic target for reducing the risk of hypoglycemia as the current findings identified its importance in the counterregulatory response to hypoglycemia. Finally, the finding that moderate hypoglycemia preconditions the brain may explain why insulin treated patients have no long-term cognitive impairments despite experiencing episodes of severe hypoglycemia. By investigating how the brain responses to both high and low blood sugar, this thesis identified critical aspects of brain glucose sensing/metabolism that modulate whole body energy and glucose homeostasis.
机译：由于葡萄糖是大脑的主要燃料来源，也是周围组织的主要营养物质，因此大脑必须感知并响应血糖变化，以维持其自身的营养需求并维持全身能量的体内平衡。脑部葡萄糖感应的破坏会导致葡萄糖耐量降低，这是糖尿病发病机理的标志，而且胰岛素治疗会导致严重低血糖的风险增加。因此，了解糖尿病对葡萄糖变化的感知和反应对糖尿病患者尤为重要。本论文中的实验研究了（1）神经元葡萄糖转运蛋白4（GLUT4）在葡萄糖传感和对低血糖的反调节反应中的作用，（2）脑对先前低血糖的适应性反应，以及（3）高血糖和下丘脑中的六胺生物合成途径（HBP）调节能量稳态。发现神经元GLUT4在调节外周胰岛素敏感性中起关键作用，并且对于引起对低血糖症的完全反调节反应是必需的。之前的中度低血糖症可进行预处理，并保护大脑免受严重低血糖症发作引起的神经元损伤和认知功能障碍的影响。最后，下丘脑中通过HBP增加的新陈代谢减少了食物摄入和体重，并增加了中枢和外周胰岛素敏感性。这些发现对糖尿病患者具有重要意义。神经元GLUT4和下丘脑HBP均可调节全身胰岛素敏感性，因此两者均可能是增强胰岛素敏感性的潜在治疗靶标，这将降低糖尿病的风险并改善糖尿病的管理。此外，接受胰岛素治疗的患者有发生低血糖症的风险。神经元GLUT4可能是降低低血糖风险的治疗靶标，因为当前的发现表明其在针对低血糖的反调节反应中的重要性。最后，中度低血糖使大脑处于先决条件的发现可能解释了尽管经历了严重的低血糖发作，但接受胰岛素治疗的患者却没有长期的认知障碍。通过研究大脑对高血糖和低血糖的反应，本论文确定了调节全身能量和葡萄糖稳态的大脑葡萄糖感测/代谢的关键方面。

著录项

  • 作者

    Puente, Erwin Calvo.;

  • 作者单位

    Washington University in St. Louis.;

  • 授予单位 Washington University in St. Louis.;
  • 学科 Biology Molecular.;Biology Neurobiology.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 148 p.
  • 总页数 148
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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