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

January 2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Simon Fisher

Abstract

As glucose is the main fuel source for the brain and a major nutrient for peripheral tissues, the brain must sense and respond to changes in blood glucose in order to sustain its own nutritional requirements and maintain whole body energy homeostasis. Disruption of brain glucose sensing results in impaired glucose tolerance, a hallmark in the pathogenesis of diabetes, as well as increased risk of severe hypoglycemia as occurs with insulin therapy. Thus, understanding how the brain senses and responds to changes in glucose is particularly important to individuals with diabetes. Experiments in this thesis investigated: 1) the role of neuronal glucose transporter 4: GLUT4) in glucose sensing and the counterregulatory response to hypoglycemia,: 2) the adaptive response of the brain to antecedent hypoglycemia, and: 3) the role of hyperglycemia and the hexosamine biosynthetic pathway: HBP) in the hypothalamus on regulating energy homeostasis. Neuronal GLUT4 was found to play a crucial role in modulating peripheral insulin sensitivity and was necessary for eliciting a full counterregulatory response to hypoglycemia. Antecedent moderate hypoglycemia preconditioned and protected the brain from neuronal injury and cognitive dysfunction induced by an episode of severe hypoglycemia. Finally, increased metabolism through the HBP in the hypothalamus decreased food intake and body weight and increased central and peripheral insulin sensitivity. These findings have important implications to individuals living with diabetes. Neuronal GLUT4 and the hypothalamic HBP both modulated whole body insulin sensitivity, and hence, both may be potential therapeutic targets to enhance insulin sensitivity, which would reduce the risk and improve management of diabetes. Further, patients on insulin therapy are at risk of experiencing hypoglycemia. Neuronal GLUT4 may be a therapeutic target for reducing the risk of hypoglycemia as the current findings identified its importance in the counterregulatory response to hypoglycemia. Finally, the finding that moderate hypoglycemia preconditions the brain may explain why insulin treated patients have no long-term cognitive impairments despite experiencing episodes of severe hypoglycemia. By investigating how the brain responses to both high and low blood sugar, this thesis identified critical aspects of brain glucose sensing/metabolism that modulate whole body energy and glucose homeostasis.

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Permanent URL: http://dx.doi.org/10.7936/K7NK3C14

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