GLUCOCORTICOIDS, HYPOGLYCEMIA & BRAIN GLUCOSE TRANSPORT

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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.