Oxyntomodulin ameliorates glucose intolerance in mice fed a high-fat diet

1 Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center; 2 Organization of Applied Scientific Research-Quality of Life, Gaubius Laboratory; 3 Department of General Internal Medicine; and 4 Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands Submitted 6 September 2007 ; accepted in final form 30 October 2007 We evaluated the acute effects of OXM on glucose metabolism in diet-induced insulin-resistant male C57Bl/6 mice. To determine the effects on glucose tolerance, mice were intraperitoneally injected with OXM (0.75, 2.5, or 7.5 nmol) or vehicle prior to an ip glucose tolerance test. OXM (0.75 nmol/h) or vehicle was infused during a hyperinsulinemic euglycemic clamp to quantify insulin action on glucose production and disposal. OXM dose-dependently improved glucose tolerance as estimated by AUC for glucose (OXM: 7.5 nmol, 1,564 ± 460, P < 0.01; 2.5 nmol, 1,828 ± 684, P < 0.01; 0.75 nmol, 2,322 ± 303, P < 0.05; control: 2,790 ± 222 mmol·l –1 ·120 min). Insulin levels in response to glucose administration were higher in 7.5 nmol OXM-treated animals compared with controls. In basal clamp conditions, OXM increased EGP (82.2 ± 14.7 vs. 39.9 ± 5.7 µmol·min –1 ·kg –1 , P < 0.001). During insulin infusion, insulin levels were twice as high in OXM-treated mice compared with controls (10.6 ± 2.8 vs. 4.4 ± 2.2 ng/ml, P < 0.01). Consequently, glucose infusion rate (118.6 ± 30.8 vs. 38.8 ± 26.4 µl/h, P < 0.001) and glucose disposal (88.1 ± 13.0 vs. 45.2 ± 6.9 µmol·min –1 ·kg –1 , P < 0.001) were enhanced in mice that received OXM. In addition, glucose production was more suppressed during OXM infusion (35.7 ± 15.5 vs. 15.8 ± 11.4% inhibition, P < 0.05). However, if these data were expressed per unit concentration of circulating insulin, OXM did not affect insulin action on glucose disposal and production. These results indicate that OXM beneficially affects glucose metabolism in diet-induced insulin-resistant C57Bl/6 mice. It ameliorates glucose intolerance, most likely because it elevates glucose-induced plasma insulin concentrations. OXM does not appear to impact on insulin action. animal model; gut hormone; glucose tolerance; insulin; hyperinsulinemic euglycemic clamp Address for reprint requests and other correspondence: E. T. Parlevliet, Leiden University Medical Center, Dept. of Endocrinology and Metabolic Diseases, P. O. Box 9600, 2300 RC Leiden, The Netherlands (e-mail: E.T.Parlevliet{at}lumc.nl )