Type 2 diabetes (T2D) is associated with chronic low-grade inflammation. We studied its mechanisms by addressing the role of inflammasomes in monocytes and their activation by circulating metabolites to produce inflammatory cytokines IL1β and IL18. Blood samples were collected from patients with T2D. Serum was filtered at 3 kDa to remove macromolecules. Inflammasome activation was analyzed by gene expression of various Nod Like Receptors by RT-quantitative PCR as well as IL1β and IL18 secretion from these monocytes in culture (ELISA). Twenty-one patients (38% women) were included in 2016. They were 57±10 years old, BMI were 33.1±6.3 kg/m2. They had T2D for 14±9 years and HbA1c at 9.5±1.2%. Their C Reactive Protein levels was 8.1±8.0 mg/L. Each subject was sampled twice at 4 days of interval: in hyperglycemia (2.56±0.86g/L) then in normoglycemia (1.23±0.41g/L). Two inflammasomes were transcripted: NLRP1 and NLRC4, with significant high level whether in normoglycemia (fold-change 1.47, p=0.01 and 1.33, p=0.02) and hyperglycemia (fold-change 1.41, p=0.02 and 1.31, p=0.04). This transcriptional priming seems to have a functional consequence with IL1β production by monocytes of some T2D patients. Healthy monocytes were collected from voluntary blood donors (Glycaemia: 0.97±0.17g/L). Incubation of them with filtered serum of T2D patients recapitulated the priming signal. The same two inflammasomes were transcripted: NLRP1 and NLRC4, whether in normoglycemia (fold-change 1.35, p=0.002 and 1.23, p=0.02) and hyperglycemia (fold-change 1.31, p=0.01 and 1.30, p=0.052). Although it did not induce activation of mature cytokines. We have shown the activation of NLRP1 and NLRC4 inflammasomes and their secretion of inflammatory cytokine in T2D patients. Some soluble serum metabolites seem directly involved in this inflammatory cascade. Our next objective will be to identify these molecules, which are potential biomarkers of predictive of chronic immune activation in T2D.
M. Monlun: None. V. Rigalleau: None. L. Blanco: None. K. Mohammedi: Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi. Other Relationship; Self; Sanofi, Takeda Development Centre Europe Ltd., Boehringer Ingelheim Pharmaceuticals, Inc.. P. Blanco: None.