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(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.
Irwin, N., Green, BD., Gault, V., Greer, B., Harriott, P., Bailey, CJ., ... O'Harte, F. (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), 1244-1250. https://doi.org/10.1021/jm049262s