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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.
Molecular metabolism, 04/2018, Volume: 10Journal Article
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. 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. 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. NLRP3 driven-pancreatic IL-1β inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D. •Inhibition of NLRP3 via MCC950 in db/db mice did not improve glucose tolerance.•MCC950 treatment did not prevent beta cell loss of function.•Expression of IL1beta and NLRP3 does not appear increased in db/db islets.•We conclude against a role for NLRP3 in db/db pancreatic dysfunction.
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