Glucose tolerance progressively declines with age whilst the onset of type two diabetes increases dramatically. Glucose-dependent insulinotropic polypeptide (GIP) potentiates glucose-induced insulin secretion. The present study was designed to assess the insulinotropic effects of a potent long-acting GIP receptor agonist, N-AcGIP(LysPAL(37)), in aging mice. In older mice, body weights, basal plasma glucose and insulin concentrations were significantly higher than in young mice (P < 0.05 to P < 0.001). Intraperitoneal injection of glucose alone (18 mmol/kg body weight) revealed a significantly lower (P < 0.05) insulin response in older mice, which was accompanied by impaired glucose tolerance (P < 0.05). Normal glucose-mediated insulin secretion was restored in N-AcGIP(LysPAL37) treated older mice. However the glycaemic excursion remained significantly, impaired in older mice (P < 0.05), suggestive of impaired insulin action. Native GIP had a similar overall effect in younger and older mice. These data indicate that N-AcGIP(LysPAL(37)) is able to counter the age-related deterioration of pancreatic beta cell glucose sensitivity and insulin secretion. (c) 2005 Elsevier Inc. All rights reserved.