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

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: Seth L Masters, Aisling Dunne, Shoba L Subramanian, Rebecca L Hull, Gillian M Tannahill, Fiona A Sharp, Christine Becker, Luigi Franchi, Eiji Yoshihara, Zhe Chen, Niamh Mullooly, Lisa A Mielke, James Harris, Rebecca C Coll, Kingston H G Mills, K Hun Mok, Philip Newsholme, Gabriel Nuñez, Junji Yodoi, Steven E Kahn, Ed C Lavelle, Luke A J O'Neill
• Journal: Nature immunology (Nat Immunol) Vol. 11 Issue 10 Pg. 897-904 (Oct 2010) ISSN: 1529-2916 [Electronic] United States
• PMID: 20835230 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amyloid
• Carrier Proteins
• Hypoglycemic Agents
• Interleukin-1beta
• Islet Amyloid Polypeptide
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• Nlrp3 protein, rat
• Receptors, Cytoplasmic and Nuclear
• Glyburide

Topics

• Amyloid (metabolism)
• Animals
• Carrier Proteins (antagonists & inhibitors, genetics, metabolism)
• Cells, Cultured
• Dendritic Cells (immunology, metabolism)
• Diabetes Mellitus, Type 2 (immunology, metabolism)
• Glyburide (pharmacology)
• Humans
• Hypoglycemic Agents (pharmacology)
• Interleukin-1beta (metabolism)
• Islet Amyloid Polypeptide
• Islets of Langerhans (metabolism)
• Macrophages (immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• NLR Family, Pyrin Domain-Containing 3 Protein
• Rats
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, genetics, metabolism)