title: A novel acylated form of (d-Ala(2))GIP with improved antidiabetic potential, lacking effect on body fat stores.
abstract: BACKGROUND
  Rapid enzymatic degradation of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), limits therapeutic use of the native peptide for diabetes. However, enzymatically stable analogues of GIP, such as (d-Ala(2))GIP, have been generated, but are still susceptible to renal filtration.
  
  
  METHODS
  The present study examines the in vitro and in vivo biological actions of a novel, acylated GIP analogue, (d-Ala(2))GIP[Lys(37)PAL].
  
  
  RESULTS
  In BRIN-BD11 cells, (d-Ala(2))GIP[Lys(37)PAL] concentration-dependently stimulated (p<0.05 to p<0.001) insulin secretion at 5.6 and 16.7mM glucose. Intraperitoneal administration of (d-Ala(2))GIP[Lys(37)PAL] to normal mice 8h prior to a glucose load significantly reduced (p<0.05) the overall glycaemic excursion compared to controls, and increased (p<0.001) the insulinotropic response compared to (d-Ala(2))GIP and saline treated high fat control mice. Once daily administration of (d-Ala(2))GIP[Lys(37)PAL] for 21days in high fat fed mice did not affect energy intake, body weight or fat deposition. However, circulating blood glucose was significantly lower (p<0.05) accompanied by increased (p<0.05) insulin concentrations by day 21. In addition, (d-Ala(2))GIP[Lys(37)PAL] treatment significantly (p<0.01) reduced the overall glycaemic excursion and increased pancreatic insulin content (p<0.05) and the insulinotropic response (p<0.01) to an exogenous glucose challenge on day 21. Chronic treatment with (d-Ala(2))GIP[Lys(37)PAL] did not result in resistance to the metabolic effects of a bolus injection of native GIP. Finally, insulin sensitivity was significantly improved (p<0.001) in (d-Ala(2))GIP[Lys(37)PAL] treated mice compared to high fat controls.
  
  
  CONCLUSIONS
  These data confirm that (d-Ala(2))GIP[Lys(37)PAL] is a stable, long-acting potent GIP agonist.
  
  
  CONCLUSIONS
  (d-Ala(2))GIP[Lys(37)PAL] may be suitable for further evaluation and future clinical development.
authors.affiliation: School of Biomedical Sciences Research Institute, University of Ulster, Coleraine, BT52 1SA, UK.
authors.forename: Christine M A
authors.initials: CM
authors.lastname: Martin
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
mesh_terms: D000818:Animals; D050218:Body Fat Distribution; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000819:agonists / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005765:Gastrointestinal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice
chemical_list: D005765:Gastrointestinal Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D005749:Gastric Inhibitory Polypeptide; D005947:Glucose