Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes

  1. Eun-Kyeong Jo1,2,4
  1. 1Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, South Korea
  2. 2Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea
  3. 3Department of Internal Medicine, Chungnam National University Hospital, Daejeon, South Korea
  4. 4Research Institute for Medical Sciences, Chungnam National University School of Medicine, Daejeon, South Korea
  1. Corresponding author: Bon Jeong Ku or Eun-Kyeong Jo, bonjeong{at}cnu.ac.kr or hayoungj{at}cnu.ac.kr

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 diabetes patients and that antidiabetic treatment with metformin contributes to modulation of inflammasome activation in type 2 diabetes.

  • Received April 11, 2012.
  • Accepted July 3, 2012.

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  1. Diabetes
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