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 glucagons 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 glucagons ability to increase glucose production. Our findings indicate that hypoglycemia increased glucagons ability to overcome insulins 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 insulins 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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07242008-150422 |
| Date | 31 July 2008 |
| Creators | Rivera Gonzalez, Noelia |
| Contributors | Alan D. Cherrington, Dr. Owen McGuinness, Dr. Mary E. Courtney Moore |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-07242008-150422/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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