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. GENERAL SIGNIFICANCE: (d-Ala(2))GIP[Lys(37)PAL] may be suitable for further evaluation and future clinical development.
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. GENERAL SIGNIFICANCE: (d-Ala(2))GIP[Lys(37)PAL] may be suitable for further evaluation and future clinical development.
Authors: Dipak Sarnobat; R Charlotte Moffett; Victor A Gault; Neil Tanday; Frank Reimann; Fiona M Gribble; Peter R Flatt; Nigel Irwin Journal: Peptides Date: 2019-11-16 Impact factor: 3.750
Authors: K Tatarkiewicz; D M Hargrove; C M Jodka; B R Gedulin; P A Smith; J A Hoyt; A Lwin; L Collins; L Mamedova; O E Levy; L D'Souza; S Janssen; V Srivastava; S S Ghosh; D G Parkes Journal: Diabetes Obes Metab Date: 2013-08-19 Impact factor: 6.577
Authors: Annie Hasib; Ming T Ng; Victor A Gault; Dawood Khan; Vadivel Parthsarathy; Peter R Flatt; Nigel Irwin Journal: Diabetologia Date: 2016-12-21 Impact factor: 10.122