title: Stable agonist of glucose-dependent insulinotropic polypeptide (GIP) restores pancreatic beta cell glucose responsiveness but not glucose intolerance in aging mice.
abstract: 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(LysPAL37), 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(LysPAL37) is able to counter the age-related deterioration of pancreatic beta cell glucose sensitivity and insulin secretion.
authors.affiliation: Diabetes Research Group, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK. n.irwin@ulster.ac.uk
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Brian D
authors.initials: BD
authors.lastname: Green
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
authors.forename: Patrick
authors.initials: P
authors.lastname: Harriot
authors.forename: Finbarr P M
authors.initials: FP
authors.lastname: O'Harte
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000375:Aging; D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D004435:Eating; D005749:Gastric Inhibitory Polypeptide / Q000819:agonists* / Q000378:metabolism / Q000494:pharmacology; D018149:Glucose Intolerance / Q000188:drug therapy*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000378:metabolism*; D020738:Leptin / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; C512327:N-AcGIP(LysPAL37); D005749:Gastric Inhibitory Polypeptide