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Title page for ETD etd-03142012-180601


Type of Document Dissertation
Author Mulligan, Kimberly Xaviera
Author's Email Address kimberly.x.mulligan@vanderbilt.edu
URN etd-03142012-180601
Title The Impact of Inflammation on the Determinants of Muscle Glucose Uptake
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
David H. Wasserman Committee Chair
Alyssa H. Hasty Committee Member
Luc Van Kaer Committee Member
Masakazu Shiota Committee Member
Keywords
  • iNOS
  • hexokinase II
  • glucose transporter 4
  • cardiac output
  • blood flow
  • insulin resistance
Date of Defense 2011-12-16
Availability unrestricted
Abstract
Skeletal muscle is an important site for the maintenance of glucose metabolism. Under insulin-stimulated conditions it accounts for ~80% of whole body glucose disposal. Muscle glucose uptake (MGU) is a three step process involving delivery of glucose from the blood to the interstitium, facilitated transport into the intracellular space by glucose transporters, and irreversible phosphorylation of glucose to glucose-6-phosphate by hexokinase. Lipopolysaccharide (LPS) elicits a strong immune response and is known to impair insulin-mediated glucose disposal. This work aims to define the mechanism by which LPS acutely impairs MGU in the conscious mouse model in vivo. Our data demonstrates decreased cardiovascular function plays a central role in the impairment of skeletal MGU caused by LPS. Using mice overexpressing key proteins involved in MGU we sought to determine if increased glucose transport or phosphorylation capacity could improve glucose uptake in the setting of acute inflammatory stress. Our data demonstrate that enhanced glucose transport, but not phosphorylation capacity, ameliorates inflammation induced impairments in MGU. The observed improvements were also associated with improved cardiovascular function. Thus LPS-induced cardiovascular alterations likely play a dominant role in modulating insulin action.
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