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

Abstract

OBJECTIVES: Type 2 diabetes (T2D) is associated with chronic, low grade inflammation. Activation of the NLRP3 inflammasome and secretion of its target interleukin-1beta (IL-1beta) have been implicated in pancreatic beta cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic beta cell death could allow for selective T2D treatment without compromising all IL-1beta-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic beta 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 beta 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-1beta 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-1beta. CONCLUSIONS: NLRP3 driven-pancreatic IL-1beta inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.

Type Journal
ISBN 2212-8778 (Electronic) 2212-8778 (Linking)
Authors Kammoun, H. L.; Allen, T. L.; Henstridge, D. C.; Barre, S.; Coll, R. C.; Lancaster, G. I.; Cron, L.; Reibe, S.; Chan, J. Y.; Bensellam, M.; Laybutt, D. R.; Butler, M. S.; Robertson, A. A. B.; O'Neill, L. A.; Cooper, M. A.; Febbraio, M. A.
Responsible Garvan Author Prof Mark Febbraio
Publisher Name Molecular Metabolism
Published Date 2018-02-07
Published Pages pii: S2212-8778
Status ePublication
DOI 10.1016/j.molmet.2018.02.001
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/29478918