Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes Academic Article uri icon

abstract

  • Interleukin 1β (IL-1β) is an important inflammatory mediator of type 2 diabetes. Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during type 2 diabetes, triggered the NLRP3 inflammasome and generated mature IL-1β. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first required priming, a process that involved glucose metabolism and was facilitated by minimally oxidized low-density lipoprotein. Finally, mice transgenic for human IAPP had more IL-1β in pancreatic islets, which localized together with amyloid and macrophages. Our findings identify previously unknown mechanisms in the pathogenesis of type 2 diabetes and treatment of pathology caused by IAPP.

authors

  • Masters, Seth L
  • Dunne, Aisling
  • Subramanian, Shoba L
  • Hull, Rebecca L
  • Tannahill, Gillian M
  • Sharp, Fiona A
  • Becker, Christine
  • Franchi, Luigi
  • Yoshihara, Eiji
  • Chen, Zhe
  • Mullooly, Niamh
  • Mielke, Lisa A
  • Harris, James
  • Coll, Rebecca C
  • Mills, Kingston HG
  • Mok, K Hun
  • Newsholme, Philip
  • Nuñez, Gabriel
  • Yodoi, Junji
  • Kahn, Steven E
  • Lavelle, Ed C
  • O'Neill, Luke AJ

publication date

  • October 2010

has subject area