Type of Document Dissertation Author Johnson, Kathryn Mercedes Stettler URN etd-04092008-163323 Title The role of physiological elevations of glucagon-like peptide-one in glucose regulation in the dog in vivo Degree PhD Department Molecular Physiology and Biophysics Advisory Committee
Advisor Name Title David Wasserman Committee Chair Alyssa Hasty Committee Member Kevin Niswender Committee Member Mary Moore Committee Member Masakazu Shiota Committee Member Keywords
- hepatic portal vein
- Glucagon-like peptide-1 -- Physiological effect
- Glucose -- Metabolism
Date of Defense 2008-04-02 Availability unrestricted AbstractGlucagon-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 ƒÒ-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.
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