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

Abstract

Aim To assess the beneficial metabolic effects of the nonapeptide hormone, arginine vasopressin (AVP), on metabolism. Materials and Methods We exchanged 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 with evaluation of receptor activation profile. Results Analogue Ac3IV, which lacked effects at the V2 receptors responsible for modulation of fluid balance, was selected as the lead compound for assessment of antidiabetic efficacy in high‐fat‐fed 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, and merit further clinical exploration.

Beneficial impact of Ac3IV, an AVP analogue acting specifically at V1a and V1b receptors, on diabetes islet morphology and transdifferentiation of alpha- and beta-cells

“…Ac3IV (Ac-CYIQNCPRG-NH 2 ), a novel enzymatically stable vasopressin analogue with introduction on an N-acetyl group, substitution of F 3 for I 3 and a disulphide bridge between the two cysteines at position 1 and 6 [ 5 ], was obtained from Synpeptide Co. Ltd. (Shanghai, China) at 95% purity. Additional peptide characterisation relating to confirmation of purity and identity was conducted in-house by HPLC and MALDI–ToF MS, as described previously [ 18 ].…”

“…Whilst V2 receptors are responsible for regulating fluid balance and osmolality [ 4 ], V1a and V1b receptors are expressed in metabolically active tissues such as the pancreas [ 3 ]. Indeed, a recently characterised enzymatically stable and long-acting AVP analogue, namely Ac3IV, that acts exclusively at V1a and V1b receptors, possesses notable exciting therapeutic potential for diabetes [ 5 ].…”

“…Accordingly, sustained activation of V1a and V1b receptor pathways by Ac3IV leads to beneficial effects on pancreatic islet architecture, as well as glucose homeostasis and overall metabolic control in high fat fed (HFF) diabetic mice [ 5 ]. Interestingly, positive effects of AC3IV on islet architecture were linked to advantageous actions on both islet cell proliferation and apoptosis [ 5 ], in direct agreement with previous in vitro observations [ 2 ].…”

“…Accordingly, sustained activation of V1a and V1b receptor pathways by Ac3IV leads to beneficial effects on pancreatic islet architecture, as well as glucose homeostasis and overall metabolic control in high fat fed (HFF) diabetic mice [ 5 ]. Interestingly, positive effects of AC3IV on islet architecture were linked to advantageous actions on both islet cell proliferation and apoptosis [ 5 ], in direct agreement with previous in vitro observations [ 2 ]. Although such islet cell turnover effects are undoubtedly important in relation to these structural changes, it is likely that preservation of islet architecture induced by Ac3IV treatment is also related to the processes of islet endocrine cell transdifferentiation [ 6 , 7 ].…”

“…The subsequent impact of 12 days pharmacological upregulation of V1a and V1b receptor pathways by Ac3IV on beta-cell lineage was then studied. We hypothesised that the pancreatic-related architectural benefits of Ac3IV in diabetes are linked to maintenance of beta-cell identity, alongside the previously observed favourable actions on islet cell proliferation and survival [ 5 ]. To examine this theory in more detail, an additional experiment was conducted that involved sustained Ac3IV treatment in STZ-diabetic Glu CreERT2 ; ROSA26-eYFP mice, a transgenic mouse model that possesses alpha-cell lineage tracing capabilities [ 9 , 12 , 17 ].…”