Evidence against a role for NLRP3-driven islet inflammation in db/db mice
Item Type:Journal Article
Citation: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., Evidence against a role for NLRP3-driven islet inflammation in db/db mice, Molecular Metabolism, 10, 2018, 66-73
1-s2.0-S2212877818300966-main.pdf (PDF) 1.063Mb
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.
Author: O'Neill, Luke; 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.; Cooper, M.A.; Febbraio, M.A.
Type of material:Journal Article
Series/Report no:Molecular Metabolism;
Availability:Full text available
Keywords:Type 2 Diabetes, IL-1βinterleukin-1β NLRP3, Nod-like receptor family pyrin domain-containing protein 3, DAMPs danger-associated molecular patterns