Antidiabetic effects of sub-chronic activation of the GIP receptor alone and in combination with background exendin-4 therapy in high fat fed mice

Regul Pept. 2009 Feb 25;153(1-3):70-6. doi: 10.1016/j.regpep.2008.11.007. Epub 2008 Dec 3.

Abstract

GLP-1 and GIP are the two key incretin hormones that regulate post-prandial glucose homeostasis. Furthermore, potent enzyme-resistant GIP and GLP-1 receptor agonists such as N-AcGIP and exendin-4 have now been developed. In the present study the effects of stable incretins, exendin-4 and N-AcGIP alone and in combination were examined in mice with high fat feeding induced glucose intolerance. Daily s.c. injections of exendin-4 (50 nmol/kg bw) for 12 days restored glycaemic control and significantly (P<0.05) decreased glucose intolerance compared to saline-treated controls. Food intake was transiently decreased (P<0.05) without effect on body weight. In the following 12 day period, mice either continued the original treatment or were administered an additional dose of N-AcGIP (50 nmol/kg body weight; s.c.). Under these circumstances sub-chronic administration of exendin-4 alone or particularly when combined with N-AcGIP significantly (P<0.05) reduced body weight. Exendin-4, N-AcGIP and combined treatment groups displayed significantly (P<0.05) decreased plasma glucose levels and less severe glucose intolerance. Non-fasting 24-h glycaemic profiles revealed marked (P<0.05 to P<0.01) beneficial effects of all treatment regimes. Insulin resistance was also reduced (P<0.01 to P<0.001) in all exendin-4 treated mice compared to saline controls. Adipose tissue mRNA levels of adiponectin, leptin, resistin, GIP-R, LPL and DGAT-1 were not significantly altered. These results illustrate efficacy of enzyme resistant GIP and GLP-1 analogues for treatment of glucose intolerance induced by high fat feeding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Diabetes Mellitus, Experimental / drug therapy*
  • Dietary Fats*
  • Eating
  • Exenatide
  • Female
  • Glucagon-Like Peptide 1 / metabolism
  • Glucose Intolerance
  • Hypoglycemic Agents / therapeutic use*
  • Insulin Resistance / physiology
  • Mice
  • Peptides / therapeutic use*
  • Receptors, Gastrointestinal Hormone / metabolism*
  • Venoms / therapeutic use*

Substances

  • Dietary Fats
  • Hypoglycemic Agents
  • Peptides
  • Receptors, Gastrointestinal Hormone
  • Venoms
  • Glucagon-Like Peptide 1
  • Exenatide
  • gastric inhibitory polypeptide receptor