Degradation, insulin secretion, glucose-lowering and GIP additive actions of a palmitate-derivatised analogue of xenin-25

Xenin-25, a K-cell derived peptide co-secreted with glucose-dependent insulinotropic polypeptide (GIP), has recently been shown to have glucose homeostatic actions and potentiate the insulinotropic effect of GIP. However, the biological actions of xenin-25 are brief due to rapid metabolism, yet little is known regarding enzymatic degradation of this peptide. Therefore, the present study has fully characterised the plasma enzymatic degradation products of xenin-25. We have also generated a novel acylated xenin-25 analogue, xenin-25(Lys(13)PAL), and evaluated its stability, biological action profile and therapeutic applicability compared to the native peptide. In contrast to xenin-25, xenin-25(Lys(13)PAL) was completely resistant to plasma enzyme degradation. Insulinotropic responses of xenin-25(Lys(13)PAL) in clonal beta-cells were similar to native xenin-25, moreover xenin-25(Lys(13)PAL) significantly (p < 0.05 to p < 0.001) potentiated the insulin releasing action of (D-Ala(2))GIP. When administered together with glucose to normal mice, the glycaemic excursion was significantly (p < 0.05) less and overall insulin secretory effect significantly (p < 0.05) greater for xenin-25(Lys(13)PAL) when compared to xenin-25 mice. Glucose-lowering and insulin releasing effects of both peptides was less prominent in high fat fed mice and ob/ob mice. However, xenin-25 significantly (p < 0.05) augmented the glucose-lowering action of (D-Ala(2))GIP in both groups of mice. Similarly, xenin-25(Lys(13)PAL) potentiated (p < 0.05) the gluco-regulatory effect of (D-Ala(2))GIP. Overall, these data indicate that palmitate-derivatised analogues of xenin-25 represent a novel class of GIP potentiator drugs for possible type 2 diabetes therapy. (C) 2012 Elsevier Inc. All rights reserved.