Degradation, insulin secretion, and antihyperglycemic actions of two palmitate-derivitized N-terminal pyroglutamyl analogues of glucose-dependent insulinotropic polypeptide

Irwin, Nigel, Green, Brian D., Gault, Victor A., Greer, Brett, Harriott, Patrick, Bailey, Clifford J., Flatt, Peter R. and O'Harte, Finbarr P.M. (2005). Degradation, insulin secretion, and antihyperglycemic actions of two palmitate-derivitized N-terminal pyroglutamyl analogues of glucose-dependent insulinotropic polypeptide. Journal of Medicinal Chemistry, 48 (4), pp. 1244-1250.

Abstract

Exploitation of glucose-dependent insulinotropic polypeptide (GIP) is hindered by its short biological half-life and rapid renal clearance. To circumvent these problems, two novel acylated N-terminally modified GIP analogues, N-pGluGIP(LysPAL16) and N-pGluGIP(LysPAL37), were evaluated. In contrast to native GIP, both analogues were completely resistant to dipeptidyl peptidase IV degradation. In GIP-receptor transfected fibroblasts, N-pGluGIP(LysPAL16) and N-pGluGIP(LysPAL37) exhibited enhanced stimulation of cAMP production. Insulinotropic responses in clonal beta-cells were similar to native GIP. When administered together with glucose to ob/ob mice, the glycemic excursions were significantly less for both analogues and insulin responses were greater than native GIP. Extended insulinotropic and antihyperglycemic actions were also evident. These data indicate that palmitate-derivitized analogues of N-terminal pyroglutamyl GIP represent a novel class of stable, long-acting, and effective GIP analogues for potential type 2 diabetes therapy.

Publication DOI: https://doi.org/10.1021/jm049262s
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences
Life & Health Sciences > Applied Health Research Group
Uncontrolled Keywords: Organic Chemistry
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Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2005
Authors: Irwin, Nigel
Green, Brian D.
Gault, Victor A.
Greer, Brett
Harriott, Patrick
Bailey, Clifford J. ( 0000-0002-6998-6811)
Flatt, Peter R.
O'Harte, Finbarr P.M.

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