GIP(Lys16PAL) and GIP(LyS37PAL)

novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potentia

Nigel Irwin, Finbarr P.M. O'Harte, Victor A. Gault, Brian D. Green, Brett Greer, Patrick Harriott, Clifford J. Bailey, Peter R. Flatt

Research output: Contribution to journalArticle

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(Lys16PAL) and GIP(Lys37PAL) 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(Lys37PAL) 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. © 2006 American Chemical Society.

Original languageEnglish
Pages (from-to)1047-1054
Number of pages8
JournalJournal of Medicinal Chemistry
Volume49
Issue number3
Early online date13 Jan 2006
DOIs
Publication statusPublished - 9 Feb 2006

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

Cite this

Irwin, Nigel ; O'Harte, Finbarr P.M. ; Gault, Victor A. ; Green, Brian D. ; Greer, Brett ; Harriott, Patrick ; Bailey, Clifford J. ; Flatt, Peter R. / GIP(Lys16PAL) and GIP(LyS37PAL) : novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potentia. In: Journal of Medicinal Chemistry. 2006 ; Vol. 49, No. 3. pp. 1047-1054.
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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(Lys16PAL) and GIP(Lys37PAL) 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(Lys37PAL) 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. {\circledC} 2006 American Chemical Society.",
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GIP(Lys16PAL) and GIP(LyS37PAL) : novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potentia. / Irwin, Nigel; O'Harte, Finbarr P.M.; Gault, Victor A.; Green, Brian D.; Greer, Brett; Harriott, Patrick; Bailey, Clifford J.; Flatt, Peter R.

In: Journal of Medicinal Chemistry, Vol. 49, No. 3, 09.02.2006, p. 1047-1054.

Research output: Contribution to journalArticle

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T1 - GIP(Lys16PAL) and GIP(LyS37PAL)

T2 - novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potentia

AU - Irwin, Nigel

AU - O'Harte, Finbarr P.M.

AU - Gault, Victor A.

AU - Green, Brian D.

AU - Greer, Brett

AU - Harriott, Patrick

AU - Bailey, Clifford J.

AU - Flatt, Peter R.

PY - 2006/2/9

Y1 - 2006/2/9

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(Lys16PAL) and GIP(Lys37PAL) 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(Lys37PAL) 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. © 2006 American Chemical Society.

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(Lys16PAL) and GIP(Lys37PAL) 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(Lys37PAL) 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. © 2006 American Chemical Society.

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