Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes
- Hye-Mi Lee1,2,
- Jwa-Jin Kim1,2,
- Hyun Jin Kim3,
- Minho Shong3,4,
- Bon Jeong Ku3,4⇓ and
- Eun-Kyeong Jo1,2,4⇓
- 1Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, South Korea
- 2Department of Microbiology, Chungnam National University School of Medicine, Daejeon, South Korea
- 3Department of Internal Medicine, Chungnam National University Hospital, Daejeon, South Korea
- 4Research Institute for Medical Sciences4, Chungnam National University School of Medicine, Daejeon, South Korea
- Corresponding author: Bon Jeong Ku, or Eun-Kyeong Jo,
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.
- Received April 11, 2012.
- Accepted July 3, 2012.
- © 2013 by the American Diabetes Association.
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