Weight reducing, lipid lowering and antidiabetic activities of a novel AVP analogue acting at V1a and V1b receptors in high fat fed mice

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Abstract

Aim: Evidence suggests beneficial metabolic effects of the nonapeptide hormone, arginine vasopressin (AVP), on metabolism, as also observed recently with the closely related oxytocin peptide.
Materials and Methods: In the current study we have exchanged selected amino acids at position 3 and 8 of AVP, namely phenylalanine and arginine, with those of oxytocin to generate novel analogues with altered receptor selectivity. Secondary modification by N-terminal acetylation was used to impart stability to circulating endopeptidases. Analogues were screened for degradation, bioactivity in rodent/human clonal beta-cells and primary murine islets together evaluation of receptor activation profile.
Results: Analogue Ac3IV, which lacked effects at V2 receptors responsible for modulation of fluid balance, was selected as the lead compound for assessment of antidiabetic efficacy in high fat fed (HFF) mice. Twice daily administration of Ac3IV, or the gold-standard control exendin-4, for 22 days reduced energy intake as well as body weight and fat content. Both interventions decreased circulating glucose levels, enhanced insulin sensitivity and substantially improved glucose tolerance and related insulin secretion in response to an intraperitoneal or oral glucose challenge. The peptides decreased total- and increased HDL-cholesterol, but only Ac3IV decreased LDL-cholesterol, triglyceride and non-fasting glucagon concentrations. Elevations of islet and beta cell areas were partially reversed, accompanied by suppressed islet cell proliferation, decreased beta-cell apoptosis and, in the case of exendin-4, also decreased alpha-cell apoptosis.
Conclusion: AVP-based therapies that exclusively target V1a and V1b receptors may have significant therapeutic potential for the treatment of obesity and related diabetes, that merits further clinical exploration.
Original languageEnglish
Article numberxx
JournalDiabetes, Obesity and Metabolism
Early online date9 Jun 2021
DOIs
Publication statusE-pub ahead of print - 9 Jun 2021

Keywords

  • Vasopressin
  • receptor selectivity
  • enzymatic stability
  • obesity
  • type 2 diabetes

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