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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amyloid / metabolism*
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Animals
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cells, Cultured
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Diabetes Mellitus, Type 2 / immunology*
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Diabetes Mellitus, Type 2 / metabolism
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Glyburide / pharmacology
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Humans
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Hypoglycemic Agents / pharmacology
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Interleukin-1beta / metabolism*
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Islet Amyloid Polypeptide
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Islets of Langerhans / metabolism
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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NLR Family, Pyrin Domain-Containing 3 Protein
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Rats
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
Substances
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Amyloid
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Carrier Proteins
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Hypoglycemic Agents
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Interleukin-1beta
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Islet Amyloid Polypeptide
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Nlrp3 protein, rat
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Receptors, Cytoplasmic and Nuclear
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Glyburide