Glucagon-like peptide-one (GLP-1) secreted from the endocrine L cell in the gut after a meal results in elevations of the peptide in arterial blood, the hepatic portal vein (~2x arterial levels) and vasculature in the gut directly surrounding the site of secretion (~4x arterial levels). An intraportal physiological bolus of GLP-1 increases afferent vagal signaling from the hepatoportal region, which could initiate the gluco-regulatory effects of GLP-1.
In Specific Aim I, hyperglycemia was induced with a combination of peripheral and intraportal glucose infusions in the 42 h fasted conscious dog. GLP-1 was given intraportally or into the hepatic artery in physiologic amounts. Intraportal, but not hepatic artery, GLP-1 delivery significantly increased nonhepatic glucose uptake relative to that observed in saline infused control dogs, without altering pancreatic hormone levels.
In Specific Aim II, GLP-1 or saline was infused intraportally in 42 h fasted conscious dogs, and hyperglycemia was induced by peripheral glucose infusion, alone. Under these conditions, GLP-1 did not alter pancreatic hormone levels or glucose utilization.
In Specific Aim III, dogs were fasted for 18 h to increase Ò-cell responsiveness and insulin sensitivity. GLP-1 or saline was infused intraportally, and hyperglycemia was induced by a combination of intraportal and peripheral glucose infusion. GLP-1 had no effect despite the presence of a portal vein glucose infusion.
In Specific Aim IV, dogs were administered a mixed meal in the presence or absence of exendin (9-39), a GLP-1R antagonist. Blocking postprandial GLP-1 action resulted in expedited gastric emptying for about 2 h which ultimately increased peripheral glycemia in both normal and insulin resistant dogs. Blocking postprandial GLP-1 action did not enhance the incretin effect in either group of animals.
In conclusion we found that in the dog 1) GLP-1R activation is not responsible for the incretin effect, 2) the dominant effect of postprandial GLP-1 secretion is slowed gastric emptying, 3) GLP-1 has a small direct effect on the liver, and 4) intraportally delivered GLP-1 induces increased nonhepatic glucose uptake under conditions that mimic a meal.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-04092008-163323 |
| Date | 05 May 2008 |
| Creators | Johnson, Kathryn Mercedes Stettler |
| Contributors | David Wasserman, Kevin Niswender, Masakazu Shiota, Alyssa Hasty, Mary 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-04092008-163323/ |
| 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. |
Page generated in 0.0018 seconds