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

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Author: Parlevliet, E.T. · Schröder-van der Elst, J.P. · Corssmit, E.P.M. · Picha, K. · O'Neil, K. · Stojanovic-Susulic, V. · Ort, T. · Havekes, L.M. · Romijn, J.A. · Pijl, H.
Type:article
Date:2009
Institution: TNO Kwaliteit van Leven
Source:Journal of Pharmacology and Experimental Therapeutics, 1, 328, 240-248
Identifier: 241347
doi: doi:10.1124/jpet.108.144154
Keywords: Biology · Biomedical Research · CNTO 736 · exendin 4 · glucagon like peptide 1 derivative · glucagon like peptide 1 receptor · very low density lipoprotein · glucagon like peptide receptor · glucagon receptor · glucagon-like peptide receptor · hybrid protein · triacylglycerol · animal experiment · animal model · chronic drug administration · controlled study · gluconeogenesis · glucose blood level · glucose transport · hyperinsulinemia · lipid diet · lipoprotein metabolism · male · mouse · nonhuman · single drug dose · animal food · blood · C57BL mouse · Cytomegalovirus · Drug effect · Drug potentiation · Fat intake · Genetics · Intravenous drug administration · Metabolism · Molecular cloning · Animal Feed · Animals · Blood Glucose · Cloning, Molecular · Cytomegalovirus · Dietary Fats · Glucose · Glucose Clamp Technique · Hyperinsulinism · Infusions, Intravenous · Insulin · Insulin Resistance · Lipoproteins, VLDL · Liver · Mice · Mice, Inbred C57BL · Promoter Regions, Genetic · Receptors, Glucagon · Recombinant Fusion Proteins · Triglycerides

Abstract

CNTO736 is a glucagon-like peptide (GLP) 1 receptor agonist that incorporates a GLP-1 peptide analog linked to the Mimeti-body 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 C57BL76 mice received a single intraperitoneal injection of CNTO736 or vehicle. Chronic effects were studied after 4 weeks of daily intraperitoneal administration. A hyperin-sulinemic- 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 μmol/min/kg) and increased insulin-mediated glucose uptake (CNTO736, 76 ± 25; control, 54 ± 13 μmol/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 μmol/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 μmol/min/kg) and VLDL production (CNTO736, 157 ± 23; control, 216 ± 36 μmol/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. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.