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

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 2 N (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 2 N, 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.

• Authors: Shruti Mohan, Andrew G McCloskey, Aine M McKillop, Peter R Flatt, Nigel Irwin, R Charlotte Moffett
• Journal: Biochimica et biophysica acta. General subjects (Biochim Biophys Acta Gen Subj) Vol. 1865 Issue 3 Pg. 129811 (03 2021) ISSN: 1872-8006 [Electronic] Netherlands
• PMID: 33309687 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Blood Glucose
• Cholesterol, HDL
• Cholesterol, LDL
• Hypoglycemic Agents
• Insulin
• Oligopeptides
• Triglycerides
• Oxytocin
• Glucagon

Topics

• Animals
• Blood Glucose (metabolism)
• Cholesterol, HDL (blood)
• Cholesterol, LDL (blood)
• Diabetes Mellitus, Experimental (blood, drug therapy, etiology, pathology)
• Diabetes Mellitus, Type 2 (blood, drug therapy, etiology, pathology)
• Diet, High-Fat (adverse effects)
• Energy Intake (drug effects, genetics)
• Female
• Glucagon (blood)
• Half-Life
• Hypoglycemic Agents (chemical synthesis, pharmacology)
• Insulin (metabolism)
• Insulin Resistance
• Insulin Secretion (drug effects)
• Islets of Langerhans (drug effects, metabolism, pathology)
• Male
• Mice
• Obesity (blood, drug therapy, etiology, pathology)
• Oligopeptides (chemical synthesis, pharmacology)
• Oxytocin (analogs & derivatives, chemical synthesis, pharmacology)
• Protein Stability
• Triglycerides (blood)