Upregulated NLRP3 Inflammasome Activation in Patients With Type 2 Diabetes

• Published in: Diabetes (New York, N.Y.) Vol. 62; no. 1; pp. 194 - 204
• Main Authors: Lee, Hye-Mi, Kim, Jwa-Jin, Kim, Hyun Jin, Shong, Minho, Ku, Bon Jeong, Jo, Eun-Kyeong
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.01.2013
• Subjects: Adult; Aged; AMP-Activated Protein Kinases - physiology; Antidiabetics; Apoptosis; Biological and medical sciences; CARD Signaling Adaptor Proteins; Care and treatment; Carrier Proteins - genetics; Carrier Proteins - physiology; Cytokines; Cytoskeletal Proteins - genetics; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Diagnosis; Dosage and administration; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Female; Glucose; Homeostasis; Humans; Immunology and Transplantation; Inflammasomes - physiology; Inflammation; Insulin resistance; Interleukin-1; Interleukin-18 - biosynthesis; Interleukin-1beta - biosynthesis; Interleukin-1beta - genetics; Kinases; Male; Medical sciences; Metformin; Metformin - therapeutic use; Middle Aged; NLR Family, Pyrin Domain-Containing 3 Protein; Obesity; Pathogenesis; Polypeptides; Protein expression; Proteins; Reactive Oxygen Species - metabolism; RNA, Messenger - analysis; Type 2 diabetes; Uric acid; South Korea; Endocrinopathy; Type 2 diabetes; Human; Metabolic diseases
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db12-0420

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.