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-1? (IL-1?) have been implicated in pancreatic ? cell failure in T2D. Specific targeting of the NLRP3 inflammasome to prevent pancreatic ? cell death could allow for selective T2D treatment without compromising all IL-1?-associated immune responses. We hypothesized that treating a mouse model of T2D with MCC950, a compound that specifically inhibits NLRP3, would prevent pancreatic ? 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 ? 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-1? 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-1?. CONCLUSIONS:NLRP3 driven-pancreatic IL-1? inflammation does not play a key role in the pathogenesis of the db/db murine model of T2D.

SUBMITTER: Kammoun HL 

PROVIDER: S-EPMC5985230 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature