Exendin-4(Lys27PAL)/gastrin/xenin-8-Gln: a novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice

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Abstract

Background: Therapeutic benefits of peptide-based drugs is limited by rapid renal elimination.
Methods: Therefore, to prolong the biological action profile of the recently characterised triple-acting hybrid peptide, exendin-4/gastrin/xenin-8-Gln, a fatty-acid (C-16) has been covalently attached, creating exendin-4(Lys27PAL)/gastrin/xenin-8-Gln. Exendin-4/gastrin and liraglutide/gastrin/xenin-8-Gln were also synthesised as direct comparator peptides.
Results: All hybrid peptides evoked significant concentration-dependent increases of insulin secretion from isolated murine islets and BRIN-BD11 cells. Following administration of peptides with glucose to mice, all hybrids significantly reduced the overall glycaemic excursion and increased insulin concentrations. In contrast to other treatments, exendin-4(Lys27PAL)/gastrin/xenin-8-Gln displayed impressive anti-hyperglycaemic actions even 12 h after administration, highlighting protracted duration of effects. Exendin-4/gastrin/xenin-8-Gln. exendin-4/gastrin, and exendin-4(Lys27PAL)/gastrin/xenin-8-Gln were then progressed to a 31-day twice-daily treatment regimen in obese-diabetic ob/ob mice. All treatments decreased non-fasting glucose and HbA1c concentrations, as well as enhancing circulating and pancreatic insulin levels. Exendin-4/gastrin and exendin-4/gastrin/xenin-8-Gln also decreased food intake. Glucose tolerance was improved by all treatments, but only exendin-4(Lys27PAL)/gastrin/xenin-8-Gln augmented glucose-induced insulin secretion. Interestingly, treatment regimens that included a xenin component induced clear advantages on the metabolic response to GIP and the glucose-lowering actions of insulin.
Conclusion: This study emphasises the therapeutic promise of long-acting, multi-targeting hybrid gut peptides for type 2 diabetes.
Original languageEnglish
Pages (from-to)e3106
JournalDiabetes/Metabolism Research and Reviews
Volume35
Issue number3
DOIs
Publication statusPublished - 30 Nov 2018

Keywords

  • Glucagon like peptide 1 (GLP-1)
  • Xenin
  • gastrin

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