CNTO736, a novel glucagon-like peptide-1 receptor agonist, ameliorates insulin resistance and inhibits very low-density lipoprotein production in high-fat-fed mice.
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.
Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases, Leiden, The Netherlands.
Edwin T
ET
Parlevliet
Janny P
JP
Schröder-van der Elst
Eleonora P M
EP
Corssmit
Kristen
K
Picha
Karyn
K
O'Neil
Vedrana
V
Stojanovic-Susulic
Tatiana
T
Ort
Louis M
LM
Havekes
Johannes A
JA
Romijn
Hanno
H
Pijl
D000821:Animal Feed; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003001:Cloning, Molecular; D003587:Cytomegalovirus / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000494:pharmacology; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism; D007262:Infusions, Intravenous; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000187:drug effects; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D018027:Receptors, Glucagon / Q000819:agonists* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism
D001786:Blood Glucose; C534787:CNTO 736; D004041:Dietary Fats; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D008079:Lipoproteins, VLDL; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D014280:Triglycerides; D005947:Glucose