Metabolic effects of sub-chronic ablation of the incretin receptors by daily administration of (Pro3)GIP and exendin(9-39)amide in obese diabetic (ob/ob) mice

Biol Chem. 2007 Feb;388(2):221-6. doi: 10.1515/BC.2007.024.

Abstract

Effects of chemical ablation of the GIP and GLP-1 receptors on metabolic aspects of obesity-diabetes were investigated using the stable receptor antagonists (Pro3)GIP and exendin(9-39)amide. Ob/ob mice received a daily i.p. injection of saline vehicle, (Pro3)GIP, exendin(9-39)amide or a combination of both peptides over a 14-day period. Non-fasting plasma glucose levels were significantly (p<0.05) lower in (Pro3)GIP-treated mice compared to control mice after just 9 days of treatment. (Pro3)GIP-treated mice also displayed significantly lower plasma glucose concentrations in response to feeding and intraperitoneal administration of either glucose or insulin (p<0.05 to p<0.001). The (Pro3)GIP-treated group also exhibited significantly (p<0.05) reduced pancreatic insulin content. Acute administration of exendin(9-39)amide immediately prior to re-feeding completely annulled the beneficial effects of sub-chronic (Pro3)GIP treatment, but non-fasting concentrations of active GLP-1 were unchanged. Combined sub-chronic administration of (Pro3GIP) with exendin(9-39)amide revealed no beneficial effects. Similarly, daily administration of exendin(9-39)amide alone had no significant effects on any of the metabolic parameters measured. These studies highlight an important role for GIP in obesity-related forms of diabetes, suggesting the possible involvement of GLP-1 in the beneficial actions of GIP receptor antagonism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / chemistry
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / metabolism*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gastric Inhibitory Polypeptide / administration & dosage*
  • Glucagon-Like Peptide-1 Receptor
  • Injections, Intraperitoneal
  • Insulin / administration & dosage
  • Insulin / chemistry
  • Insulin / metabolism
  • Mice
  • Mice, Obese
  • Obesity / complications
  • Obesity / metabolism*
  • Peptide Fragments / administration & dosage*
  • Receptors, Gastrointestinal Hormone / chemistry
  • Receptors, Gastrointestinal Hormone / drug effects
  • Receptors, Gastrointestinal Hormone / metabolism*
  • Receptors, Glucagon / chemistry
  • Receptors, Glucagon / drug effects
  • Receptors, Glucagon / metabolism*
  • Structure-Activity Relationship
  • Time Factors

Substances

  • Blood Glucose
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Peptide Fragments
  • Receptors, Gastrointestinal Hormone
  • Receptors, Glucagon
  • glucose-dependent insulinotropic polypeptide, Pro(3)-
  • exendin (9-39)
  • Gastric Inhibitory Polypeptide
  • gastric inhibitory polypeptide receptor