Exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln: A novel acylated GLP-1/gastrin/xenin hybrid peptide that improves metabolic status in obese-diabetic (ob/ob) mice

Diabetes Metab Res Rev. 2019 Mar;35(3):e3106. doi: 10.1002/dmrr.3106. Epub 2018 Dec 19.

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 characterized triple-acting hybrid peptide, exendin-4/gastrin/xenin-8-Gln, a fatty acid (C-16) has been covalently attached, creating exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln. Exendin-4/gastrin and liraglutide/gastrin/xenin-8-Gln were also synthesized 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(Lys27 PAL)/gastrin/xenin-8-Gln displayed impressive antihyperglycaemic actions even 12 hours after administration, highlighting protracted duration of effects. Exendin-4/gastrin/xenin-8-Gln, exendin-4/gastrin, and exendin-4(Lys27 PAL)/gastrin/xenin-8-Gln were then progressed to a 31-day twice-daily treatment regimen in obese-diabetic ob/ob mice. All treatments decreased nonfasting 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(Lys27 PAL)/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 glucose-dependent insulinotropic polypeptide (GIP) and the glucose-lowering actions of insulin.

Conclusion: This study emphasizes the therapeutic promise of long-acting, multi-targeting hybrid gut peptides for type 2 diabetes.

Keywords: gastrin; glucagon-like peptide-1 (GLP-1); xenin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acylation
  • Animals
  • Exenatide / chemistry*
  • Gastrins / chemistry*
  • Glucagon-Like Peptide 1 / chemistry*
  • Insulin / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Obesity / drug therapy
  • Obesity / metabolism*
  • Peptide Fragments / administration & dosage*
  • Peptide Fragments / chemistry
  • Thinness*

Substances

  • Gastrins
  • Insulin
  • Peptide Fragments
  • xenin-8
  • Glucagon-Like Peptide 1
  • Exenatide