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Fatty acid derivatisation was used to develop two novel, long-acting, N-terminally modified, glucose-dependent insulinotropic polypeptide (GIP) analogues,  N -AcGIP(LysPAL 16 ) and  N -AcGIP(LysPAL 37 ). In contrast to GIP, which was rapidly degraded by  in vitro  incubation with dipeptidylpeptidase IV (DPP IV) (52% intact after 2 h), the analogues remained fully intact for up to 24 h. Both fatty acid-derivatised analogues stimulated cAMP production in GIP receptor Chinese hamster lung (CHL) fibroblasts (EC 50  12.1–13.0 nM) and significantly improved  in vitro  insulin secretion from BRIN-BD11 cells (1.1- to 2.4-fold;  p &lt;0.05 to  p &lt;0.001) compared to control (5.6 mM glucose). Administration of  N -AcGIP(LysPAL 16 ) and  N -AcGIP(LysPAL 37 ) together with glucose in obese diabetic ( ob/ob ) mice significantly reduced the glycaemic excursion (1.4- and 1.5-fold, respectively;  p &lt;0.05 to  p &lt;0.01) and improved the insulinotropic response (1.5- and 2.3-fold, respectively;  p &lt;0.01 to  p &lt;0.001) compared to native peptide. Dose-response studies with  N -AcGIP(LysPAL 37 ) revealed that even the lowest concentration (6.25 nmol/kg) induced a highly significant decrease (1.4-fold;  p &lt;0.001) in the overall glycaemic excursion, coupled with a significant increase (2.0-fold;  p &lt;0.01) in circulating insulin. Furthermore, basal glucose values remained significantly reduced ( p &lt;0.05) and insulin values increased 24 h following a single injection of  N -AcGIP(LysPAL 37 ). The glucose-lowering action of the fatty acid-derivatised peptide was greater than that of  N -AcGIP. These data demonstrate that novel fatty acid-derivatised analogues of N-terminally modified AcGIP function as long-acting GIP-receptor agonists, with significant antidiabetic potential.

biological chemistry

Antidiabetic potential of two novel fatty acid derivatised, N-terminally modified analogues of glucose-dependent insulinotropic polypeptide (GIP):  N -AcGIP(LysPAL 16 ) and  N -AcGIP(LysPAL 37 )