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

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          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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          Author and article information

          Journal
          J. Med. Chem.
          Journal of medicinal chemistry
          American Chemical Society (ACS)
          0022-2623
          0022-2623
          Feb 24 2005
          : 48
          : 4
          Affiliations
          [1 ] School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, UK.
          Article
          10.1021/jm049262s
          15715491
          86df310f-72e0-4bcd-9f9d-40807c28bc0e
          History

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