title: Degradation, insulin secretion, glucose-lowering and GIP additive actions of a palmitate-derivatised analogue of xenin-25.
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(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.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, UK.
authors.forename: Christine M A
authors.initials: CM
authors.lastname: Martin
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
authors.forename: Stephen
authors.initials: S
authors.lastname: McClean
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism* / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008969:Molecular Sequence Data; D009496:Neurotensin / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010168:Palmitates / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010168:Palmitates; C077659:xenin 25; D009496:Neurotensin; D005749:Gastric Inhibitory Polypeptide