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.
LanguageEnglish
Pagese3106
JournalDiabetes/Metabolism Research and Reviews
Volume35
Issue number3
DOIs
Publication statusPublished - 30 Nov 2018

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Glucagon-Like Peptide 1
Gastrins
Peptides
Insulin
Glucose
exenatide
xenin 25
xenin-8
Type 2 Diabetes Mellitus
Fatty Acids
Eating

Keywords

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

Cite this

@article{00b12d1a1e7043f48f7883ecc62c8c36,
title = "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",
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.",
keywords = "Glucagon like peptide 1 (GLP-1), Xenin, gastrin",
author = "Annie Hasib and Tony NG and Neil Tanday and Sarah Craig and Gault, {Victor A} and PR Flatt and Nigel Irwin",
year = "2018",
month = "11",
day = "30",
doi = "10.1002/dmrr.3106",
language = "English",
volume = "35",
pages = "e3106",
journal = "Diabetes/Metabolism Research and Reviews",
issn = "1520-7552",
number = "3",

}

TY - JOUR

T1 - 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

AU - Hasib, Annie

AU - NG, Tony

AU - Tanday, Neil

AU - Craig, Sarah

AU - Gault, Victor A

AU - Flatt, PR

AU - Irwin, Nigel

PY - 2018/11/30

Y1 - 2018/11/30

N2 - 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.

AB - 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.

KW - Glucagon like peptide 1 (GLP-1)

KW - Xenin

KW - gastrin

U2 - 10.1002/dmrr.3106

DO - 10.1002/dmrr.3106

M3 - Article

VL - 35

SP - e3106

JO - Diabetes/Metabolism Research and Reviews

T2 - Diabetes/Metabolism Research and Reviews

JF - Diabetes/Metabolism Research and Reviews

SN - 1520-7552

IS - 3

ER -