Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5823900 | Biochemical Pharmacology | 2012 | 8 Pages |
Abstract
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(Lys13PAL), and evaluated its stability, biological action profile and therapeutic applicability compared to the native peptide. In contrast to xenin-25, xenin-25(Lys13PAL) was completely resistant to plasma enzyme degradation. Insulinotropic responses of xenin-25(Lys13PAL) in clonal beta-cells were similar to native xenin-25, moreover xenin-25(Lys13PAL) significantly (p < 0.05 to p < 0.001) potentiated the insulin releasing action of (D-Ala2)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(Lys13PAL) 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-Ala2)GIP in both groups of mice. Similarly, xenin-25(Lys13PAL) potentiated (p < 0.05) the gluco-regulatory effect of (D-Ala2)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.
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Authors
Christine M.A. Martin, Victor A. Gault, Stephen McClean, Peter R. Flatt, Nigel Irwin,