• Irwin, Nigel
  • Green, BD
  • Gault, Victor
  • Harriot, P
  • O'Harte, Finbarr
  • Flatt, Peter

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Stable agonist of glucose-dependent insulinotropic polypeptide (GIP) restores pancreatic beta cell glucose responsiveness but not glucose intolerance in aging mice




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.