Published in:
01-06-2015 | Original Article
Xenin-25[Lys13PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential
Published in: Acta Diabetologica | Issue 3/2015
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Aims
Xenin-25 is co-secreted with glucose-dependent insulinotropic polypeptide (GIP) from intestinal K-cells following a meal.
Xenin-25 is believed to play a key role in glucose homoeostasis and potentiate the insulinotropic effect of GIP.
Methods
This study investigated the effects of sub-chronic administration of the stable and longer-acting xenin-25 analogue, xenin-25[Lys13PAL] (25 nmol/kg), in diabetic mice fed with a high-fat diet.
Results
Initial studies confirmed the significant persistent glucose-lowering (p < 0.05) and insulin-releasing (p < 0.05) actions of xenin-25[Lys13PAL] compared with native xenin-25. Interestingly, xenin-25 retained significant glucose-lowering activity in GIP receptor knockout mice. Twice-daily intraperitoneal (i.p.) injection of xenin-25[Lys13PAL] for 14 days had no significant effect on food intake or body weight in high-fat-fed mice. Non-fasting glucose and insulin levels were also unchanged, but overall glucose levels during an i.p. glucose tolerance and oral nutrient challenge were significantly (p < 0.05) lowered by xenin-25[Lys13PAL] treatment. These changes were accompanied by significant improvements in i.p. (p < 0.05) and oral (p < 0.001) nutrient-stimulated insulin concentrations. No appreciable changes in insulin sensitivity were observed between xenin-25[Lys13PAL] and saline-treated high-fat mice. However, xenin-25[Lys13PAL] treatment restored notable sensitivity to the biological actions of exogenous GIP injection. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were not altered by 14-day twice-daily treatment with xenin-25[Lys13PAL]. In contrast, ambulatory activity was significantly (p < 0.05 to p < 0.001) increased during the dark phase in xenin-25[Lys13PAL] mice compared with high-fat controls.
Conclusions
These data indicate that sustained administration of a stable analogue of xenin-25 exerts a spectrum of beneficial metabolic effects in high-fat-fed mice.