Print Email Facebook Twitter CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice Title CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice 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. TNO Kwaliteit van Leven Publication year 2009 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. Subject BiologyBiomedical ResearchCNTO 736exendin 4glucagon like peptide 1 derivativeglucagon like peptide 1 receptorvery low density lipoproteinglucagon like peptide receptorglucagon receptorglucagon-like peptide receptorhybrid proteintriacylglycerolanimal experimentanimal modelchronic drug administrationcontrolled studygluconeogenesisglucose blood levelglucose transporthyperinsulinemialipid dietlipoprotein metabolismmalemousenonhumansingle drug doseanimal foodbloodC57BL mouseCytomegalovirusDrug effectDrug potentiationFat intakeGeneticsIntravenous drug administrationMetabolismMolecular cloningAnimal FeedAnimalsBlood GlucoseCloning, MolecularCytomegalovirusDietary FatsGlucoseGlucose Clamp TechniqueHyperinsulinismInfusions, IntravenousInsulinInsulin ResistanceLipoproteins, VLDLLiverMiceMice, Inbred C57BLPromoter Regions, GeneticReceptors, GlucagonRecombinant Fusion ProteinsTriglycerides To reference this document use: http://resolver.tudelft.nl/uuid:7303251b-345d-4b3c-8ef4-f11ff56f17ff DOI https://doi.org/10.1124/jpet.108.144154 TNO identifier 241347 ISSN 0022-3565 Source Journal of Pharmacology and Experimental Therapeutics, 328 (1), 240-248 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.