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

. 2005 Feb 24;48(4):1244-50.

doi: 10.1021/jm049262s.

Affiliations

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

Nigel Irwin et al. J Med Chem. 2005.

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(LysPAL(16)) and N-pGluGIP(LysPAL(37)), were evaluated. In contrast to native GIP, both analogues were completely resistant to dipeptidyl peptidase IV degradation. In GIP-receptor transfected fibroblasts, N-pGluGIP(LysPAL(16)) and N-pGluGIP(LysPAL(37)) 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.

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