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Evidence against a role for NLRP3-driven islet inflammation in db/db mice

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Kammoun, HL, Allen, TL, Henstridge, DC ORCID: 0000-0003-4988-767X, Barre, S, Coll, RC, Lancaster, GI, Cron, L, Reibe, S, Chan, JY, Bensellam, M, Laybutt, DR, Butler, MS, Robertson, AAB, O'Neill, LA, Cooper, MA and Febbraio, MA 2018 , 'Evidence against a role for NLRP3-driven islet inflammation in db/db mice' , Molecular Metabolism, vol. 10 , pp. 66-73 , doi: 10.1016/j.molmet.2018.02.001.

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Abstract

Objectives: Type 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1β (IL-1β) have been implicated in pancreatic β cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic β cell death could allow for selective T2D treatment without compromising all IL-1β-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic β cell death, thereby preventing the onset of T2D. Methods: Diabetic db/db mice were treated with MCC950 via drinking water for 8 weeks from 6 to 14 weeks of age, a period over which they developed pancreatic β cell failure. We assessed metabolic parameters such as body composition, glucose tolerance, or insulin secretion over the course of the intervention.Results: MCC950 was a potent inhibitor of NLRP3-induced IL-1β in vitro and was detected at high levels in the plasma of treated db/db mice. Treatment of pre-diabetic db/db mice with MCC950, however, did not prevent pancreatic dysfunction and full onset of the T2D pathology. When examining the NLRP3 pathway in the pancreas of db/db mice, we could not detect an activation of this pathway nor increased levels of its target IL-1β. Conclusions: NLRP3 driven-pancreatic IL-1β inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.

Item Type: Article
Authors/Creators:Kammoun, HL and Allen, TL and Henstridge, DC and Barre, S and Coll, RC and Lancaster, GI and Cron, L and Reibe, S and Chan, JY and Bensellam, M and Laybutt, DR and Butler, MS and Robertson, AAB and O'Neill, LA and Cooper, MA and Febbraio, MA
Keywords: db/db mice, inflammasome, interleukin-1 beta, MCC950, type 2 diabetes, antidiabetic agent, cryopyrin, insulin, unclassified drug, antidiabetic agent, anti-inflammatory agent, cryopyrin, fused heterocyclic rings
Journal or Publication Title: Molecular Metabolism
Publisher: Elsevier BV
ISSN: 2212-8778
DOI / ID Number: 10.1016/j.molmet.2018.02.001
Copyright Information:

Copyright 2018 The Authors. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) https://creativecommons.org/licenses/by-nc-nd/4.0/

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