204-OR: An Early Immune Signature in Prediabetes Can Predict Progression to Type 2 Diabetes

Inflammation promotes conversion from metabolically healthy to type 2 diabetes (T2D) in animal models, but convincing demonstrations of this relationship have not been reported in people. We aimed at identifying the cellular and cytokine profile of immune cells, as major sources of inflammation, during progression to T2D. We studied subjects who did or did not convert to T2D in a longitudinal observational cohort study (APT-2D), where drug naïve individuals without T2D at baseline (with normoglycemia or prediabetes) are monitored for disease progression by assessing metabolic function every 6 months for 3 years or until conversion to T2D. Immune cell composition in peripheral blood was studied at baseline and at the point of T2D diagnosis. Correlation analysis was conducted between changes in cell frequency and metabolic parameters: Glycated hemoglobin (HbA1c), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR); fasting insulin (FI); insulin-mediated glucose disposal (M/I); and acute insulin response (AIR). Thirty-two converters aged 49.5 ± 1.6 years with BMI 28.8 ± 0.8 kg/m2 were studied, along with sixty-four non-converters matched for age, gender, and ethnicity. At baseline, our results revealed lower frequencies of classical monocytes and type 2 conventional dendritic cells among converters compared to non-converters, which correlated negatively with HbA1c, HOMA-IR and FI and positively with AIR. At onset of T2D, frequencies of CD8+ and CD4+ naïve T cells, CD19+ B cells, and basophils increased in converters compared to their pre-conversion state and among them CD4+ naïve T cell and CD19+ B cell frequencies correlated negatively with HOMA-IR and FI. Stimulated PBMCs from converters compared to non-converters at baseline produced lower amounts of cytokines (TNFa, IL17A, IL17F, TGFb, IFNg), which did not change after conversion to T2D. Flow cytometric and cytokine profiling thus indicated that changes in immune cell function in prediabetes is linked to T2D conversion.