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Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1ß 2 in type 2 diabetes

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Authors
Masters, S.
Dunne, A.
Subramanian, S.
Hull, R.
Tannahill, G.
Sharp, F.
Becker, C.
Franchi, L.
Yoshihara, E.
Chen, Z.
Mullooly, N.
Mielke, L.
Harris, J.
Coll, R.
Mills, K.
Mok, K.
Newsholme, Philip
Nuñez, G.
Yodoi, J.
Kahn, S.
Lavelle, E.
O'Neill, L.
Date
2010
Type
Journal Article

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Citation
Masters, S. and Dunne, A. and Subramanian, S. and Hull, R. and Tannahill, G. and Sharp, F. and Becker, C. et al. 2010. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1ß 2 in type 2 diabetes. Nature Immunology. 11 (10): pp. 897-904.
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Nature Immunology
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School of Biomedical Sciences
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Abstract

Interleukin 1ß 2 (IL-1ß 2) 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-1ß 2. One therapy for type 2 diabetes, glyburide, suppressed IAPP-mediated IL-1ß 2 production in vitro. Processing of IL-1ß 2 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-1ß 2 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.