GIP(Lys(16)PAL) and GIP(LyS(37)PAL): Novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potential

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

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34 Citations (Scopus)

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys(16)PAL) and GIP(Lys(37)PAL) were resistant to dipeptidyl peptidase IV (DPP IV) degradation. In vitro studies demonstrated that GIP analogues retained their ability to activate the GIP receptor through production of cAMP and to stimulate insulin secretion. Intraperitoneal administration of GIP analogues to obese diabetic (ob/ob) mice significantly decreased the glycemic excursion and elicited increased and prolonged insulin responses compared to native GIP. A protracted glucose-lowering effect was observed 24 h following GIP(LyS(37)PAL) administration. Once a day injection for 14 days decreased nonfasting glucose, improved glucose tolerance, and enhanced the insulin response to glucose. These data demonstrate that fatty acid derivatized GIP peptides represent a novel class of long-acting stable GIP analogues for therapy of type 2 diabetes.
LanguageEnglish
Pages1047-1054
JournalJournal of Medicinal Chemistry
Volume49
Issue number3
DOIs
Publication statusPublished - Feb 2006

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Hypoglycemic Agents
Glucose
Peptides
Insulin
Fatty Acids
Gastric Inhibitory Polypeptide
Dipeptidyl Peptidase 4
Serum Albumin
Type 2 Diabetes Mellitus

Cite this

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title = "GIP(Lys(16)PAL) and GIP(LyS(37)PAL): Novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potential",
abstract = "Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys(16)PAL) and GIP(Lys(37)PAL) were resistant to dipeptidyl peptidase IV (DPP IV) degradation. In vitro studies demonstrated that GIP analogues retained their ability to activate the GIP receptor through production of cAMP and to stimulate insulin secretion. Intraperitoneal administration of GIP analogues to obese diabetic (ob/ob) mice significantly decreased the glycemic excursion and elicited increased and prolonged insulin responses compared to native GIP. A protracted glucose-lowering effect was observed 24 h following GIP(LyS(37)PAL) administration. Once a day injection for 14 days decreased nonfasting glucose, improved glucose tolerance, and enhanced the insulin response to glucose. These data demonstrate that fatty acid derivatized GIP peptides represent a novel class of long-acting stable GIP analogues for therapy of type 2 diabetes.",
author = "Nigel Irwin and Finbarr O'Harte and Victor Gault and BD Green and B Greer and P Harriott and CJ Bailey and Peter Flatt",
year = "2006",
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TY - JOUR

T1 - GIP(Lys(16)PAL) and GIP(LyS(37)PAL): Novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potential

AU - Irwin, Nigel

AU - O'Harte, Finbarr

AU - Gault, Victor

AU - Green, BD

AU - Greer, B

AU - Harriott, P

AU - Bailey, CJ

AU - Flatt, Peter

PY - 2006/2

Y1 - 2006/2

N2 - Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys(16)PAL) and GIP(Lys(37)PAL) were resistant to dipeptidyl peptidase IV (DPP IV) degradation. In vitro studies demonstrated that GIP analogues retained their ability to activate the GIP receptor through production of cAMP and to stimulate insulin secretion. Intraperitoneal administration of GIP analogues to obese diabetic (ob/ob) mice significantly decreased the glycemic excursion and elicited increased and prolonged insulin responses compared to native GIP. A protracted glucose-lowering effect was observed 24 h following GIP(LyS(37)PAL) administration. Once a day injection for 14 days decreased nonfasting glucose, improved glucose tolerance, and enhanced the insulin response to glucose. These data demonstrate that fatty acid derivatized GIP peptides represent a novel class of long-acting stable GIP analogues for therapy of type 2 diabetes.

AB - Glucose-dependent insulinotropic polypeptide (GIP) is a physiological insulin releasing peptide. We have developed two novel fatty acid derivatized GIP analogues, which bind to serum albumin and demonstrate enhanced duration of action in vivo. GIP(Lys(16)PAL) and GIP(Lys(37)PAL) were resistant to dipeptidyl peptidase IV (DPP IV) degradation. In vitro studies demonstrated that GIP analogues retained their ability to activate the GIP receptor through production of cAMP and to stimulate insulin secretion. Intraperitoneal administration of GIP analogues to obese diabetic (ob/ob) mice significantly decreased the glycemic excursion and elicited increased and prolonged insulin responses compared to native GIP. A protracted glucose-lowering effect was observed 24 h following GIP(LyS(37)PAL) administration. Once a day injection for 14 days decreased nonfasting glucose, improved glucose tolerance, and enhanced the insulin response to glucose. These data demonstrate that fatty acid derivatized GIP peptides represent a novel class of long-acting stable GIP analogues for therapy of type 2 diabetes.

U2 - 10.1021/jm0509997

DO - 10.1021/jm0509997

M3 - Article

VL - 49

SP - 1047

EP - 1054

JO - Journal of Medicinal Chemistry

T2 - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 3

ER -