GLUCOCORTICOIDS, HYPOGLYCEMIA & BRAIN GLUCOSE TRANSPORT

糖皮质激素，低血糖

• 批准号: 6178641
• 负责人: ANTHONY L MCCALL
• 金额: $ 20.89万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6178641
• 关键词: RNase protection assay; brain metabolism; cerebral cortex; corticosterone; gene expression; glucose transport; glucose transporter; hippocampus; hormone regulation /control mechanism; hypoglycemia; hypothalamus; immunocytochemistry; in situ hybridization; insulin; laboratory rabbit; laboratory rat; messenger RNA; metyrapone; pathologic process; stress; western blottings

Hypoglycemia is the barrier to excellent glycemic control for many patients with diabetes, especially those with Type 1 diabetes. The inability to perceive hypoglycemia, hypoglycemia unawareness, and the inability to mount a protective counter- insulin hormonal defense--- defective counterregulation--- are the most important risk factors for repeated and serious hypoglycemia in those with diabetes. Recent evidence from several differing lines of investigation suggest a common hormonal mechanism affecting the brain could underlie much of hypoglycemia unawareness and defective counterregulation. First, glucocorticoid stress hormones may be important in inducing hypoglycemia unawareness and defective counterregulation. Second, transport of nutrient glucose into brain cells may also underlie these two interrelated phenomena. Third, certain key areas of the brain, in particular the ventromedial hypothalamus and hippocampus, may be involved in the defective signal transduction that underlies hypoglycemia unawareness and defective counterregulation. Fourth, preliminary work shows that glucocorticoids modify brain glucose transporter expression. Thus, the studies proposed will test the hypothesis that hypoglycemia induces glucocorticoid stress hormones and that by doing so, these hormones help to alter brain glucose transport and metabolism in key areas of the brain that are a major basis for subsequent, defective counter-insulin protective hormonal responses. This project's specific aims are to: 1. Determine how mild and more marked stress levels of corticosterone administered to rats affect regional expression of brain GLUT1 and GLUT3 protein and mRNA. 2. Determine how repeated hypoglycemia affects regional brain GLUT1 and GLUT3 protein and mRNA expression. 3. Determine how stress levels of corticosterone administered to rats and chronic insulin hypoglycemia affect hypoglycemia-induced stress responses. 4. Determine how pharmacological blockade of glucocorticoid secretion after insulin hypoglycemia affects brain expression of GLUT1 and GLUT3 and hypoglycemia counterregulation. We will test whether the ventromedial hypothalamus and hippocampal formation, in particular, are subject to regulation of brain glucose transport proteins as a result of chronic hypoglycemia and glucocorticoid excess. With high affinity antibodies suitable for fine immunocytochemical localization, our lab is uniquely able to assess precise anatomic localization of brain glucose transporter changes. We will assess in rats the counterregulation response to a single bout of hypoglycemia after prior chronic hypoglycemia. We will test whether glucocorticoid treatment induces similar defective counterregulation after hypoglycemia. Finally, we will assess whether blockade of hypoglycemia induced glucocorticoid excess may prevent altered brain GLUT expression in these key areas and thereby prevent defective counterregulation responses to acute hypoglycemia. These studies should provide insight into hypoglycemia's impact upon the brain. They may potentially lead to safer was to achieve good diabetes control.

低血糖是许多糖尿病患者（尤其是 1 型糖尿病患者）实现良好血糖控制的障碍。 无法感知低血糖、低血糖无意识以及无法建立保护性抗胰岛素激素防御（反调节缺陷）是糖尿病患者反复发生严重低血糖的最重要危险因素。 最近来自几个不同研究领域的证据表明，影响大脑的一种常见激素机制可能是低血糖无意识和有缺陷的反调节的基础。 首先，糖皮质激素应激激素可能在诱发低血糖无意识和反调节缺陷方面发挥重要作用。其次，营养物质葡萄糖向脑细胞的运输也可能是这两种相互关联的现象的基础。 第三，大脑的某些关键区域，特别是下丘脑腹内侧和海马，可能涉及导致低血糖无意识和有缺陷的反调节的缺陷信号转导。 第四，初步工作表明糖皮质激素可以改变大脑葡萄糖转运蛋白的表达。因此，提出的研究将检验这样的假设：低血糖会诱导糖皮质激素应激激素，并且通过这样做，这些激素有助于改变大脑关键区域的葡萄糖转运和代谢，这是随后有缺陷的抗胰岛素保护性激素反应的主要基础。 该项目的具体目标是： 1. 确定给予大鼠的轻度和更显着的皮质酮应激水平如何影响大脑 GLUT1 和 GLUT3 蛋白和 mRNA 的区域表达。 2. 确定反复低血糖如何影响大脑区域 GLUT1 和 GLUT3 蛋白及 mRNA 表达。 3. 确定给予大鼠的皮质酮应激水平和慢性胰岛素低血糖如何影响低血糖引起的应激反应。 4. 确定胰岛素低血糖后药理学阻断糖皮质激素分泌如何影响 GLUT1 和 GLUT3 的脑表达以及低血糖反调节。我们将测试下丘脑腹内侧区和海马结构是否会因慢性低血糖和糖皮质激素过量而受到大脑葡萄糖转运蛋白的调节。 凭借适合精细免疫细胞化学定位的高亲和力抗体，我们的实验室能够评估脑葡萄糖转运蛋白变化的精确解剖定位。我们将在大鼠中评估先前慢性低血糖后对单次低血糖的反调节反应。 我们将测试糖皮质激素治疗是否会在低血糖后引起类似的有缺陷的反调节。 最后，我们将评估阻断低血糖引起的糖皮质激素过量是否可以防止这些关键区域大脑 GLUT 表达的改变，从而防止对急性低血糖的有缺陷的反调节反应。这些研究应该可以深入了解低血糖对大脑的影响。 它们可能会导致更安全地实现良好的糖尿病控制。