GLUCOCORTICOIDS, HYPOGLYCEMIA & BRAIN GLUCOSE TRANSPORT

糖皮质激素，低血糖

• 批准号: 6590245
• 负责人: ANTHONY L MCCALL
• 金额: $ 20.88万
• 依托单位: UNIVERSITY OF VIRGINIA
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6590245
• 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.

对于许多糖尿病患者，尤其是1型糖尿病患者，低血糖是获得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的反胰岛素激素防御-有缺陷的反调节-是糖尿病患者反复和严重低血糖的最重要危险因素。 最近的证据从几个不同的调查线表明，一个共同的激素机制影响大脑可能是基础的低血糖无意识和有缺陷的反调节。 首先，糖皮质激素应激激素可能在诱导低血糖无意识和反调节缺陷中起重要作用。其次，营养葡萄糖进入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，特别是腹内侧下丘脑和海马，可能参与了导致低血糖无意识和反调节缺陷的缺陷信号转导。 第四，初步研究表明糖皮质激素可调节脑葡萄糖转运蛋白的表达。因此，所提出的研究将检验低血糖诱导糖皮质激素应激激素的假设，并且通过这样做，这些激素有助于改变大脑关键区域的大脑葡萄糖转运和代谢，这是随后的有缺陷的反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。确定给予大鼠的皮质酮的轻度和更明显的应激水平如何影响大脑GLUT 1和GLUT 3蛋白和mRNA的局部表达。 2.确定反复低血糖如何影响局部脑GLUT 1和GLUT 3蛋白和mRNA表达。 3.确定大鼠皮质酮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.确定胰岛素低血糖后糖皮质激素分泌的药物阻断如何影响GLUT 1和GLUT 3的脑表达以及低血糖的反调节。我们将测试是否腹内侧下丘脑和海马结构，特别是，是受调节的大脑葡萄糖转运蛋白作为慢性低血糖和糖皮质激素过量的结果。 我们的实验室拥有适合精细免疫细胞化学定位的高亲和力抗体，能够独特地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对先前慢性低血糖后的单次低血糖发作的反调节反应。 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反调节缺陷。 最后，我们将评估阻断低血糖诱导的糖皮质激素过量是否可以防止这些关键区域的脑GLUT表达改变，从而防止对急性低血糖的不良反调节反应。这些研究应该提供深入了解低血糖对大脑的影响。 他们可能会导致更安全的是实现良好的糖尿病控制。