TY - JOUR
T1 - Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP)
T2 - N-AcGIP(LysPAL16) and N-AcGIP(LysPAL37)
AU - Irwin, N
AU - Gault, VA
AU - Green, BD
AU - Greer, B
AU - Harriott, P
AU - Bailey, Clifford
AU - Flatt, PR
AU - O'Harte, FPM
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-Ac-GIP(LysPAL16) and N-AcGIP(LysPAL37). 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-Ac-GIP(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-Ac-GIP(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 N-AcGIP(LysPAL37). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of N-AcGIP. 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. Copyright © by Walter de Gruyter 2005 All Rights Reserved.
AB - Fatty acid derivatisation was used to develop two novel, long-acting, N-terminally modified, glucose-dependent insulinotropic polypeptide (GIP) analogues, N-Ac-GIP(LysPAL16) and N-AcGIP(LysPAL37). 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-Ac-GIP(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-Ac-GIP(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 N-AcGIP(LysPAL37). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of N-AcGIP. 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. Copyright © by Walter de Gruyter 2005 All Rights Reserved.
KW - dipeptidylpeptidase IV (DPP IV)
KW - fatty acid derivatisation
KW - GIP analogues
KW - glucose-dependent insulinotropic polypeptide (GIP)
KW - insulin secretion
KW - obese diabetic ob/ob mice
UR - http://www.scopus.com/inward/record.url?scp=26844564654&partnerID=8YFLogxK
UR - http://www.degruyter.com/view/j/bchm.2005.386.issue-7/bc.2005.079/bc.2005.079.xml
U2 - 10.1515/BC.2005.079
DO - 10.1515/BC.2005.079
M3 - Article
C2 - 16207089
SN - 1437-4315
VL - 386
SP - 679
EP - 687
JO - Biological Chemistry
JF - Biological Chemistry
IS - 7
ER -