Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Molecular Cell Biology

Language

English (en)

Date of Award

Spring 2-14-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Simon J Fisher

Abstract

Glucose homeostasis can be peripherally and centrally mediated. Within the periphery, GLUT4 in muscle and adipose tissue is required for normal glucose homeostasis and disruption of GLUT4 translocation in these tissues leads to glucose intolerance and insulin resistance, hallmarks of Type 2 diabetes. Within the brain, specialized glucose sensing neurons regulate whole body glucose homeostasis. Unlike GLUT4's role in the periphery, brain GLUT4 regulation of glucose tolerance is not well defined. Understanding how brain glucose sensing, mediated by GLUT4, regulates glucose tolerance and insulin sensitivity will aid in the development of treatment strategies to protect against the pathogenesis of diabetes. In addition, the brain regulates hypoglycemic counterregulation. Hypoglycemia is a major limitation to the treatment of diabetes. Severe hypoglycemia can lead to brain damage, cognitive dysfunction, and death. Understanding how to prevent the complications of severe hypoglycemia is critical to helping patients that are at risk. This thesis investigated 1) the role of brain GLUT4 in mediating peripheral insulin sensitivity, brain glucose sensing, and the counterregulatory response to hypoglycemia, 2) the effect of chronic insulin therapy in protecting the diabetic brain against neuronal damage and cognitive dysfunction due to severe hypoglycemia, and 3) the mechanisms by which severe hypoglycemia leads to sudden death. Brain GLUT4 was shown to be critical for normal glucose homeostasis and the counterregulatory response to hypoglycemia. This indicates that therapeutic targeting strategies can aim to enhance brain GLUT4 function to improve glucose homeostasis in the setting of diabetes. Chronic insulin therapy in diabetic rats decreased the extent of brain damage due to severe hypoglycemia. This indicates that insulin therapy in diabetes decreases susceptibility to severe hypoglycemia-induced brain damage. The mechanisms of severe hypoglycemia induced sudden death are shown for the first time to be regulated by sympathetic mediated fatal cardiac arrhythmias. This thesis reveals the importance of the brain in the regulation of glucose homeostasis and the counterregulatory response to hypoglycemia and reveals paradoxical evidence that inhibition of the counterregulatory response acts to protect against severe hypoglycemia-induced mortality.

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Permanent URL: http://dx.doi.org/10.7936/K7XW4GS6

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