Published in
Nature Research, Nature Immunology, 10(11), p. 897-904, 2010
DOI: 10.1038/ni.1935
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Activation of the Nlrp3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes
,
Aisling Dunne,
Shoba L. Subramanian,
Rebecca L. Hull,
Gillian M. Tannahill,
Fiona A. Sharp,
Christine E. Becker,
Luigi Franchi,
Eiji Yoshihara,
Zhe Chen,
Niamh Mullooly,
Lisa A. Mielke ,
James Harris,
Rebecca Clare Coll,
Kingston H. G. Mills
and other authors.
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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.