GLUCOCORTICOIDS, HYPOGLYCEMIA & BRAIN GLUCOSE TRANSPORT

糖皮质激素，低血糖

• 批准号: 6074968
• 负责人: ANTHONY L MCCALL
• 金额: $ 21.01万
• 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/6074968
• 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，特别是1型糖尿病患者良好血糖控制的障碍。不能察觉低血糖，不知道低血糖，以及无法建立保护性的反胰岛素激素防御-有缺陷的反调节-是糖尿病患者反复发生严重低血糖的最重要的危险因素。最近来自几个不同研究方向的证据表明，影响大脑的一种共同的荷尔蒙机制可能是低血糖、意识不清和反调节缺陷的主要原因。首先，糖皮质激素应激激素可能是导致低血糖意识不清和反调节缺陷的重要因素。其次，营养葡萄糖向脑细胞的运输也可能是这两个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体，可能参与了导致低血糖意识和反调节缺陷的信号转导缺陷。第四，初步研究表明，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一个假设，即低血糖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运输和新陈代谢，这是随后有缺陷的抗胰岛素保护性激素反应的主要基础。本项目的具体目标是：1.确定给予大鼠轻度和较明显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.确定反复低血糖对局部脑GLUT1和GLUT3蛋白和mRNA表达的影响。3.确定给予大鼠皮质酮的应激水平和慢性胰岛素低血糖如何影响低血糖诱导的应激反应。4.确定药物阻断胰岛素低血糖后糖皮质激素分泌对脑内GLUT1和GLUT3表达的影响以及低血糖的反调节作用。我们将测试由于慢性低血糖和糖皮质激素过量，特别是下丘脑腹内侧和海马结构是否受到大脑葡萄糖运输蛋白的调节。凭借适合精细免疫细胞化学定位的高亲和力抗体，我们的实验室唯一能够评估大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在既往慢性低血糖后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缺陷反调节。最后，我们将评估阻断糖皮质激素过量引起的低血糖是否可以防止这些关键区域大脑过度表达的改变，从而防止对急性低血糖的有缺陷的反调节反应。这些研究应该能深入了解低血糖对大脑的影响。它们可能导致更安全的是实现良好的糖尿病控制。