CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice

J Pharmacol Exp Ther. 2009 Jan;328(1):240-8. doi: 10.1124/jpet.108.144154. Epub 2008 Oct 10.

Abstract

CNTO736 is a glucagon-like peptide (GLP) 1 receptor agonist that incorporates a GLP-1 peptide analog linked to the Mimetibody platform. We evaluate the potential of acute and chronic CNTO736 treatment on insulin sensitivity and very low-density lipoprotein (VLDL) metabolism. For acute studies, diet-induced insulin-resistant C57BL/6 mice received a single intraperitoneal injection of CNTO736 or vehicle. Chronic effects were studied after 4 weeks of daily intraperitoneal administration. A hyperinsulinemic-euglycemic clamp monitored insulin sensitivity. A single dose of CNTO736 reduced fasting plasma glucose levels (CNTO736, 4.4 +/- 1.0; control, 6.3 +/- 2.4 mM) and endogenous glucose production (EGP) (CNTO736, 39 +/- 11; control, 53 +/- 13 micromol/min/kg) and increased insulin-mediated glucose uptake (CNTO736, 76 +/- 25; control, 54 +/- 13 micromol/min/kg). Chronic administration of CNTO736 reduced fasting glucose levels (CNTO736, 4.1 +/- 0.8; control 6.0 +/- 1.0 mM), improved insulin-dependent glucose uptake (CNTO736, 84 +/- 19; control, 61 +/- 15 micromol/min/kg), and enhanced inhibition of EGP (CNTO736, 91 +/- 18; control, 80 +/- 10% inhibition). In addition, chronic dosing with CNTO736 reduced fasting EGP (CNTO736, 39 +/- 9; control, 50 +/- 8 micromol/min/kg) and VLDL production (CNTO736, 157 +/- 23; control, 216 +/- 36 micromol/h/kg). These results indicate that CNTO736 reinforces insulin's action on glucose disposal and production in diet-induced insulin-resistant mice. In addition, CNTO736 reduces basal hepatic glucose and VLDL output in these animals. The data suggest that CNTO736 may be a useful tool in the treatment of type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Feed
  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Cloning, Molecular
  • Cytomegalovirus / genetics
  • Dietary Fats / pharmacology*
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / pharmacology
  • Glucose Clamp Technique
  • Hyperinsulinism
  • Infusions, Intravenous
  • Insulin / administration & dosage
  • Insulin / blood
  • Insulin / pharmacology
  • Insulin Resistance / physiology*
  • Lipoproteins, VLDL / blood*
  • Lipoproteins, VLDL / drug effects
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / genetics
  • Recombinant Fusion Proteins / administration & dosage
  • Recombinant Fusion Proteins / pharmacology*
  • Triglycerides / metabolism

Substances

  • Blood Glucose
  • CNTO 736
  • Dietary Fats
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Lipoproteins, VLDL
  • Receptors, Glucagon
  • Recombinant Fusion Proteins
  • Triglycerides
  • Glucose