QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.108.144154v1 328/1/240    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Parlevliet, E. T. Articles by Pijl, H. Search for Related Content PubMed PubMed Citation Articles by Parlevliet, E. T. Articles by Pijl, H.

METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

CNTO736, a Novel Glucagon-Like Peptide-1 Receptor Agonist, Ameliorates Insulin Resistance and Inhibits Very Low-Density Lipoprotein Production in High-Fat-Fed Mice

Departments of Endocrinology and Metabolic Diseases (E.T.P., J.P.S.-v.d.E., E.P.M.C., L.M.H., J.A.R., H.P.), Internal Medicine (L.M.H., H.P.), and Cardiology (L.M.H.), Leiden University Medical Center, Leiden, The Netherlands; Centocor R&D, Inc., Discovery Research, Radnor, Pennsylvania (K.P., K.O., V.S.-S., T.O.); and Organization of Applied Scientific Research-Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands (L.M.H.)

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 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.

Address correspondence to: Hanno Pijl, Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases. P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: h.pijl{at}lumc.nl