Glucose-dependent insulinotropic polypeptide (GIP) is a key hormone of the enteroinsular axis. The present study was designed to assess the metabolic effects in healthy mice of long term activation of the GIP receptor by N-AcGlp(LySpAL(37)), a potent long-acting GIP receptor agonist. Daily injection of N-AcGIP(LysPAL(37)) (25 nmoVkg body weight) for 14 days had no significant effect on food intake, body weight, glycated hemoglobin levels, non-fasting plasma glucose and insulin concentrations compared to saline treated controls. No significant differences in post-prandial plasma glucose and insulin concentrations were observed between the two groups following 15 min feeding. However, after 14 days, the glycemic response to intraperitoneal (i.p.) glucose was significantly improved in the NAcGIP(LysPAL(37)) treated mice compared to controls (P <0.01). In keeping with this, glucose-mediated insulin secretion was significantly enhanced in the N-AcGIP(LyspAL(37)) treated group (P <0.05). No changes in insulin sensitivity or pancreatic insulin content of the NAcGIP(LysPAL(37)) treated mice were detected. No adverse reactions were noted and the effects of N-AcGIP(LysPAL(37)) were reversed by 14 days cessation of treatment. These data indicate that long term activation of the GIP receptor by daily treatment with N-AcGIP(LysPAL(37)) improved glucose tolerance due to enhancement of pancreatic beta cell glucose responsiveness and insulin secretion. (c) 2005 Elsevier Inc. All rights reserved.