Xenin-25[Lys13PAL]: a novel long-acting acylated analogue of xenin-25 with promising antidiabetic potential.

Abstract

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[Lys(13)PAL] (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[Lys(13)PAL] 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[Lys(13)PAL] 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[Lys(13)PAL] 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[Lys(13)PAL] and saline-treated high-fat mice. However, xenin-25[Lys(13)PAL] 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[Lys(13)PAL]. In contrast, ambulatory activity was significantly (p < 0.05 to p < 0.001) increased during the dark phase in xenin-25[Lys(13)PAL] 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.

• Authors: V A Gault, C M A Martin, P R Flatt, V Parthsarathy, N Irwin
• Journal: Acta diabetologica (Acta Diabetol) Vol. 52 Issue 3 Pg. 461-71 (Jun 2015) ISSN: 1432-5233 [Electronic] Germany
• PMID: 25374384 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• xenin 25
• Neurotensin
• Oxygen

Topics

• Acetylation
• Animals
• Blood Glucose (metabolism)
• Diabetes Mellitus, Experimental (drug therapy)
• Disease Models, Animal
• Energy Metabolism
• Humans
• Hypoglycemic Agents (administration & dosage, chemistry)
• Male
• Mice
• Neurotensin (administration & dosage, chemistry)
• Oxygen (metabolism)