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, Evidence against a role for NLRP3-driven islet inflammation in db/db mice, Molecular Metabolism, 10 pp. 66-73. ISSN 2212-8778 (2018) [Refereed Article]
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/
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:||Refereed Article|
|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|
|Research Division:||Biological Sciences|
|Research Group:||Biochemistry and cell biology|
|Research Field:||Cell metabolism|
|Objective Group:||Clinical health|
|Objective Field:||Clinical health not elsewhere classified|
|UTAS Author:||Henstridge, DC (Mr Darren Henstridge)|
|Web of Science® Times Cited:||20|
|Deposited By:||Health Sciences|
|Downloads:||6 View Download Statistics|
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