The Avpr1a (V1a) and Avpr1b (V1b) receptor selective, vasopressin (AVP) analogue, Ac3IV has been shown to improve metabolism and pancreatic islet structure in diabetes and insulin resistance. The present study further investigates these actions by assessing the ability of Ac3IV to protect against pancreatic islet architectural disturbances induced by hydrocortisone (HC) treatment in transgenic Ins1^Cre/+;Rosa26-eYFP mice, that possess beta-cell lineage tracing capabilities. HC intervention increased (p < 0.001) energy intake but reduced (p < 0.01) body weight gain, with no impact of Ac3IV. All HC mice had reduced (p < 0.05) circulating glucose, but plasma insulin and glucagon concentrations remained unchanged. However, HC mice presented with increased (p < 0.001) pancreatic insulin content, which was further augmented by Ac3IV. In addition, Ac3IV treatment countered HC-induced increases in islet-, beta- and alpha-cell areas (p < 0.01), as well as promoting islet number towards control levels. This was accompanied by reduced (p < 0.05) beta-cell growth, but enhanced (p < 0.001) alpha-cell proliferation. There were no changes in islet cell apoptotic rates in any of the groups of HC mice, but co-expression of CK19 with insulin in pancreatic ductal cells was reduced by Ac3IV. Assessment of beta-cell lineage revealed that Ac3IV partially protected against HC-mediated de-differentiation of mature beta-cells, whilst also decreasing (p < 0.01) beta- to alpha-cell transdifferentiation. Our data indicate that sustained activation of V1a and V1b receptors exerts positive islet cell transition effects to help retain beta-cell identity in HC mice.

2021-10-01·Diabetes, Obesity and Metabolism

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

Article

作者: Mohan, Shruti ; Irwin, Nigel ; Flatt, Peter R. ; Moffett, R. Charlotte

AbstractAimTo assess the beneficial metabolic effects of the nonapeptide hormone, arginine vasopressin (AVP), on metabolism.Materials and MethodsWe 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.ResultsAnalogue 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.ConclusionAVP‐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.

2021-02-01·Journal of Cardiac Failure2区 · 医学

Dual Vasopressin Receptor Antagonism to Improve Congestion in Patients With Acute Heart Failure: Design of the AVANTI Trial

2区 · 医学

Article

作者: Dinh, Wilfried ; Goldsmith, Steven R ; Kolkhof, Peter ; Staedtler, Gerald ; Zannad, Faiez ; Gustafsson, Finn ; Colorado, Pablo ; Burkhoff, Daniel ; Voors, Adriaan ; Udelson, James E

BACKGROUNDLoop diuretics are the main treatment for patients with acute heart failure, but are associated with neurohormonal stimulation and worsening renal function and do not improve long-term outcomes. Antagonists to arginine vasopressin may provide an alternative strategy to avoid these effects. The AVANTI study will investigate the efficacy and safety of pecavaptan, a novel, balanced dual-acting V1a/V2 vasopressin antagonist, both as adjunctive therapy to loop diuretics after admission for acute heart failure, and later as monotherapy.METHODS AND RESULTSAVANTI is a double-blind, randomized phase II study in 571 patients hospitalized with acute heart failure and signs of persistent congestion before discharge. In part A, patients will receive either pecavaptan 30 mg/d or placebo with standard of care for 30 days. In part B, eligible patients will continue treatment or receive pecavaptan or diuretics as monotherapy for another 30 days. The primary end points for part A are changes in body weight and serum creatinine; for part B, changes in body weight and blood urea nitrogen/creatinine ratio.CONCLUSIONSThis study will provide the first evidence that a balanced V1a/V2 antagonist may safely enhance decongestion, both as an adjunct to loop diuretics and as an alternative strategy.TRIAL REGISTRATION NUMBERNCT03901729.

100 项与 Ac3IV 相关的药物交易

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