title: Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes.
abstract: Despite the recent attention focused on the roles of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in the pathogenesis of type 2 diabetes, little is known about the ex vivo profile of inflammasome activation in type 2 diabetic patients. In this study, we investigated patterns of NLRP3 inflammasome activation in monocyte-derived macrophages (MDMs) from drug-naïve patients with newly diagnosed type 2 diabetes. Type 2 diabetic subjects had significantly increased mRNA and protein expression of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and proinflammatory cytokines in MDMs cultured with autologous sera compared with healthy controls. Upregulated interleukin (IL)-1β maturation, IL-18 secretion, and caspase-1 cleavage were observed in MDMs from type 2 diabetic patients after stimulation with various danger molecules (ATP, high-mobility group protein B1, free fatty acids, islet amyloid polypeptide, and monosodium uric acid crystals). Mitochondrial reactive oxygen species and NLRP3 were required for IL-1β synthesis in MDMs. Finally, 2 months of therapy with the antidiabetic drug metformin significantly inhibited the maturation of IL-1β in MDMs from patients with type 2 diabetes through AMP-activated protein kinase (AMPK) activation. Taken together, these data suggest that NLRP3 inflammasome activation is elevated in myeloid cells from type 2 diabetic patients and that antidiabetic treatment with metformin contributes to modulation of inflammasome activation in type 2 diabetes.
authors.affiliation: Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, South Korea.
authors.forename: Hye-Mi
authors.initials: HM
authors.lastname: Lee
authors.forename: Jwa-Jin
authors.initials: JJ
authors.lastname: Kim
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.forename: Bon Jeong
authors.initials: BJ
authors.lastname: Ku
authors.forename: Eun-Kyeong
authors.initials: EK
authors.lastname: Jo
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology; D000328:Adult; D000368:Aged; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D020382:Interleukin-18 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D008687:Metformin; D055372:AMP-Activated Protein Kinases