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Title page for ETD etd-07242008-150422


Type of Document Master's Thesis
Author Rivera Gonzalez, Noelia
Author's Email Address noelia.rivera@vanderbilt.edu
URN etd-07242008-150422
Title The sensitivity of the liver to glucagon is increased during insulin-induced hypoglycemia
Degree Master of Science
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Dr. Owen McGuinness Committee Chair
Alan D. Cherrington Committee Member
Dr. Mary E. Courtney Moore Committee Member
Keywords
  • hepatic glucose production
  • gluconeogenesis
  • glycogenolysis
  • Glucagon
  • insulin-induced hypoglycemia
  • Insulin -- Physiological effect
Date of Defense 2008-07-18
Availability unrestricted
Abstract
Hypoglycemia often results from insulin excess. The counterregulatory response to hypoglycemia involves the release of glucagon, epinephrine, norepinephrine and cortisol which increase glucose production. Glucagon is the primary hormone involved in the response of glucose production to hypoglycemia, but during prolonged hypoglycemia the other hormones also become important regulators of this process. Nevertheless, under severe hypoglycemic conditions glucagon is the most important regulator of glucose production despite the presence of high insulin levels. In contrast, under euglycemic conditions insulin is a potent inhibitor of glucagon’s effect on the liver. In other words, glucagon is more effective in the presence of hypoglycemia than in the presence of euglycemia despite high insulin levels. The first aim of this work was to determine the extent to which hypoglycemia augments glucagon’s ability to increase glucose production. Our findings indicate that hypoglycemia increased glucagon’s ability to overcome insulin’s inhibitory effect on hepatic glucose production 2.3 fold. This effect was attributable to a marked (almost 3-fold) enhancement of net glycogen breakdown. The second aim of the work was to determine the molecular mechanism by which this effect came about. In that regard it was associated with a 2.3 fold increase in the ability of glucagon to reduce the phosphorylation of GSK3â caused by insulin. At the same time hypoglycemia decreased insulin’s ability to bring about the phosphorylation of Akt. Thus a combination of decreased insulin signaling and increased action of glucagon which reduced the phosphorylation of GSK-3â caused an increase in net hepatic glycogen breakdown. The physiologic trigger for the increased sensitivity of the liver to glucagon during insulin-induced hypoglycemia remains to be determined.
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