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

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.

• Authors: Edwin T Parlevliet, Janny P Schröder-van der Elst, Eleonora P M Corssmit, Kristen Picha, Karyn O'Neil, Vedrana Stojanovic-Susulic, Tatiana Ort, Louis M Havekes, Johannes A Romijn, Hanno Pijl
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 328 Issue 1 Pg. 240-8 (Jan 2009) ISSN: 1521-0103 [Electronic] United States
• PMID: 18849357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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