Development and characterisation of novel, enzymatically stable oxytocin analogues with beneficial antidiabetic effects in high fat fed mice

Shruti Mohan, A McCloskey, Aine McKillop, PR Flatt, Nigel Irwin, Charlotte Moffett

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Background: There is growing evidence to support beneficial effects of the hypothalamic synthesised hormone, oxytocin, on metabolism. However, the biological half-life of oxytocin is short and receptor activation profile unspecific. Methods: We have characterised peptide-based oxytocin analogues with structural modifications aimed at improving half-life and receptor specificity. Following extensive in vitro and in vivo characterisation, antidiabetic efficacy of lead peptides was examined in high fat fed (HFF) mice.Results: Following assessment of stability against enzymatic degradation, insulin secretory activity, receptor activation profile and in vivo bioactivity, analogues 2N (Ac-C ˂YIQNC >PLG-NH2) and D7R ((D-C)YIQNCYLG-NH2) were selected as lead peptides. Twice daily injection of either peptide for 22 days reduced body weight, energy intake, plasma glucose and insulin and pancreatic glucagon content in HFF mice. In addition, both peptides reduced total- and LDL-cholesterol, with concomitant elevations of HDL-cholesterol, and D7R also decreased triglyceride levels. The two oxytocin analogues improved glucose tolerance and insulin responses to intraperitoneal, and particularly oral, glucose challenge on day 22. Both oxytocin analogues enhanced insulin sensitivity, reduced HOMA-IR and increased bone mineral density. In terms of pancreatic islet histology, D7R reversed high fat feeding induced elevations of islet and beta cell areas, which was associated with reductions in beta cell apoptosis. Islet insulin secretory responsiveness was improved by 2N, and especially D7R, treatment. Conclusion: Novel, enzymatically stable oxytocin analogues exert beneficial antidiabetic effects in HFF mice.General significance: These observations emphasise the, yet untapped, therapeutic potential of long-acting oxytocin-based agents for obesity and type 2 diabetes.
Original languageEnglish
Article number129811
Pages (from-to)1-12
Number of pages12
JournalBIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS
Volume1865
Issue number3
Early online date10 Dec 2020
DOIs
Publication statusPublished - 31 Mar 2021

Bibliographical note

Funding Information:
These studies were supported by Ulster University Vice-Chancellor and Diabetes UK funded PhD research scholarships, an early career research award from Diabetes UK and Ulster University selective research funding.

Publisher Copyright:
© 2020 Elsevier B.V.

Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.

Keywords

  • Oxytocin
  • oxytocin analogues
  • obesity
  • type 2 diabetes

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