Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP): N-AcGIP(LysPAL(16)) and N-AcGIP(LysPAL(37))

Nigel Irwin, Victor Gault, BD Green, B Greer, P Harriott, CJ Bailey, Finbarr O'Harte, Peter Flatt

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Fatty acid derivatisation was used to develop two novel, long-acting, N-terminally modified, glucose-dependent insulinotropic polypeptide (GIP) analogues, N-AcGIP(LysPAL(16))and N-AcGIP(LysPAL(37)). In contrast to GIP, which was rapidly degraded by in vitro incubation with dipeptidylpeptidase IV (DPP IV) (52% intact after 2 h), the analogues remained fully intact for up to 24 h. Both fatty acid-derivatised analogues stimulated cAMP production in GIP receptor Chinese hamster lung (CHL) fibroblasts (EC50 12.1-13.0 nm) and significantly improved in vitro insulin secretion from BRIN-BD11 cells (1.1- to 2.4-fold; p <0.05 to p <0.001) compared to control (5.6 mm glucose). Administration of N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37) together with glucose in obese diabetic (ob/ob) mice significantly reduced the glycaemic excursion (1.4- and 1.5-fold, respectively; p <0.05 to p <0.01) and improved the insulinotropic response (1.5- and 2.3-fold, respectively; p <0.01 to p <0.001) compared to native peptide. Dose-response studies with N-AcGIP(LysPAL37) revealed that even the lowest concentration (6.25 nmol/kg) induced a highly significant decrease (1.4-fold; p <0.001) in the overall glycaemic excursion, coupled with a significant increase (2.0-fold; p <0.01) in circulating insulin. Furthermore, basal glucose values remained significantly reduced (p <0.05) and insulin values increased 24 h following a single injection of NAcGIP(LysPAL(37)). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of NAcGIP. These data demonstrate that novel fatty acid-derivatised analogues of N-terminally modified AcGIP function as long-acting GIP-receptor agonists, with significant antidiabetic potential.
LanguageEnglish
Pages679-687
JournalBiological Chemistry
Volume386
Issue number7
DOIs
Publication statusPublished - Jul 2005

Fingerprint

Hypoglycemic Agents
Fatty Acids
Glucose
Peptides
Insulin
Cricetulus
Fibroblasts
Lung
Injections

Cite this

@article{bb9c92b0af1943e588f49e201d5fc872,
title = "Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP): N-AcGIP(LysPAL(16)) and N-AcGIP(LysPAL(37))",
abstract = "Fatty acid derivatisation was used to develop two novel, long-acting, N-terminally modified, glucose-dependent insulinotropic polypeptide (GIP) analogues, N-AcGIP(LysPAL(16))and N-AcGIP(LysPAL(37)). In contrast to GIP, which was rapidly degraded by in vitro incubation with dipeptidylpeptidase IV (DPP IV) (52{\%} intact after 2 h), the analogues remained fully intact for up to 24 h. Both fatty acid-derivatised analogues stimulated cAMP production in GIP receptor Chinese hamster lung (CHL) fibroblasts (EC50 12.1-13.0 nm) and significantly improved in vitro insulin secretion from BRIN-BD11 cells (1.1- to 2.4-fold; p <0.05 to p <0.001) compared to control (5.6 mm glucose). Administration of N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37) together with glucose in obese diabetic (ob/ob) mice significantly reduced the glycaemic excursion (1.4- and 1.5-fold, respectively; p <0.05 to p <0.01) and improved the insulinotropic response (1.5- and 2.3-fold, respectively; p <0.01 to p <0.001) compared to native peptide. Dose-response studies with N-AcGIP(LysPAL37) revealed that even the lowest concentration (6.25 nmol/kg) induced a highly significant decrease (1.4-fold; p <0.001) in the overall glycaemic excursion, coupled with a significant increase (2.0-fold; p <0.01) in circulating insulin. Furthermore, basal glucose values remained significantly reduced (p <0.05) and insulin values increased 24 h following a single injection of NAcGIP(LysPAL(37)). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of NAcGIP. These data demonstrate that novel fatty acid-derivatised analogues of N-terminally modified AcGIP function as long-acting GIP-receptor agonists, with significant antidiabetic potential.",
author = "Nigel Irwin and Victor Gault and BD Green and B Greer and P Harriott and CJ Bailey and Finbarr O'Harte and Peter Flatt",
year = "2005",
month = "7",
doi = "10.1515/BC.2005.079",
language = "English",
volume = "386",
pages = "679--687",
journal = "Biological Chemistry",
issn = "1431-6730",
number = "7",

}

TY - JOUR

T1 - Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP): N-AcGIP(LysPAL(16)) and N-AcGIP(LysPAL(37))

AU - Irwin, Nigel

AU - Gault, Victor

AU - Green, BD

AU - Greer, B

AU - Harriott, P

AU - Bailey, CJ

AU - O'Harte, Finbarr

AU - Flatt, Peter

PY - 2005/7

Y1 - 2005/7

N2 - Fatty acid derivatisation was used to develop two novel, long-acting, N-terminally modified, glucose-dependent insulinotropic polypeptide (GIP) analogues, N-AcGIP(LysPAL(16))and N-AcGIP(LysPAL(37)). In contrast to GIP, which was rapidly degraded by in vitro incubation with dipeptidylpeptidase IV (DPP IV) (52% intact after 2 h), the analogues remained fully intact for up to 24 h. Both fatty acid-derivatised analogues stimulated cAMP production in GIP receptor Chinese hamster lung (CHL) fibroblasts (EC50 12.1-13.0 nm) and significantly improved in vitro insulin secretion from BRIN-BD11 cells (1.1- to 2.4-fold; p <0.05 to p <0.001) compared to control (5.6 mm glucose). Administration of N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37) together with glucose in obese diabetic (ob/ob) mice significantly reduced the glycaemic excursion (1.4- and 1.5-fold, respectively; p <0.05 to p <0.01) and improved the insulinotropic response (1.5- and 2.3-fold, respectively; p <0.01 to p <0.001) compared to native peptide. Dose-response studies with N-AcGIP(LysPAL37) revealed that even the lowest concentration (6.25 nmol/kg) induced a highly significant decrease (1.4-fold; p <0.001) in the overall glycaemic excursion, coupled with a significant increase (2.0-fold; p <0.01) in circulating insulin. Furthermore, basal glucose values remained significantly reduced (p <0.05) and insulin values increased 24 h following a single injection of NAcGIP(LysPAL(37)). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of NAcGIP. These data demonstrate that novel fatty acid-derivatised analogues of N-terminally modified AcGIP function as long-acting GIP-receptor agonists, with significant antidiabetic potential.

AB - Fatty acid derivatisation was used to develop two novel, long-acting, N-terminally modified, glucose-dependent insulinotropic polypeptide (GIP) analogues, N-AcGIP(LysPAL(16))and N-AcGIP(LysPAL(37)). In contrast to GIP, which was rapidly degraded by in vitro incubation with dipeptidylpeptidase IV (DPP IV) (52% intact after 2 h), the analogues remained fully intact for up to 24 h. Both fatty acid-derivatised analogues stimulated cAMP production in GIP receptor Chinese hamster lung (CHL) fibroblasts (EC50 12.1-13.0 nm) and significantly improved in vitro insulin secretion from BRIN-BD11 cells (1.1- to 2.4-fold; p <0.05 to p <0.001) compared to control (5.6 mm glucose). Administration of N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37) together with glucose in obese diabetic (ob/ob) mice significantly reduced the glycaemic excursion (1.4- and 1.5-fold, respectively; p <0.05 to p <0.01) and improved the insulinotropic response (1.5- and 2.3-fold, respectively; p <0.01 to p <0.001) compared to native peptide. Dose-response studies with N-AcGIP(LysPAL37) revealed that even the lowest concentration (6.25 nmol/kg) induced a highly significant decrease (1.4-fold; p <0.001) in the overall glycaemic excursion, coupled with a significant increase (2.0-fold; p <0.01) in circulating insulin. Furthermore, basal glucose values remained significantly reduced (p <0.05) and insulin values increased 24 h following a single injection of NAcGIP(LysPAL(37)). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of NAcGIP. These data demonstrate that novel fatty acid-derivatised analogues of N-terminally modified AcGIP function as long-acting GIP-receptor agonists, with significant antidiabetic potential.

U2 - 10.1515/BC.2005.079

DO - 10.1515/BC.2005.079

M3 - Article

VL - 386

SP - 679

EP - 687

JO - Biological Chemistry

T2 - Biological Chemistry

JF - Biological Chemistry

SN - 1431-6730

IS - 7

ER -