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A novel acylated form of (d-Ala2)GIP with improved antidiabetic potential, lacking effect on body fat stores

Biochimica et Biophysica Acta (BBA) - General Subjects
DOI: 10.1016/j.bbagen.2013.03.011
  • Glucose-Dependent Insulinotropic Polypeptide (Gip)
  • Analogue
  • Acylation
  • Type 2 Diabetes
  • Glucose Tolerance
  • Insulin Secretion
  • Biology
  • Medicine


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-Ala2)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-Ala2)GIP[Lys37PAL]. Results In BRIN-BD11 cells, (d-Ala2)GIP[Lys37PAL] concentration-dependently stimulated (p<0.05 to p<0.001) insulin secretion at 5.6 and 16.7mM glucose. Intraperitoneal administration of (d-Ala2)GIP[Lys37PAL] 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-Ala2)GIP and saline treated high fat control mice. Once daily administration of (d-Ala2)GIP[Lys37PAL] 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-Ala2)GIP[Lys37PAL] 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-Ala2)GIP[Lys37PAL] 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-Ala2)GIP[Lys37PAL] treated mice compared to high fat controls. Conclusions These data confirm that (d-Ala2)GIP[Lys37PAL] is a stable, long-acting potent GIP agonist. General significance (d-Ala2)GIP[Lys37PAL] may be suitable for further evaluation and future clinical development.

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