Introduction and Objective: Type 2 diabetes (T2D) is a heterogeneous disease, with an extensive clinical diversity. While many classifications of T2D have been proposed in recent years, none incorporate inflammatory parameters, despite the critical role of inflammation in the pathogenesis of T2D. In this study, we aim to integrate circulating immune cells (CIC) characterization to define T2D endotypes with distinct immuno-inflammatory profiles.Methods: A total of 3100 T2D participants, including 405 newly-diagnosed ones, were recruited from the Angiosafe cohort. An unsupervised clustering method (k-means) based on CIC counts (neutrophils, monocytes, and lymphocytes) was applied to identify T2D endotypes. Multi-omics approaches, including targeted proteomics, transcriptomics, and epigenomics, were utilized to characterize the nature and intensity of the immune response in these endotypes. We projected subsequently two longitudinal validation cohorts of 700 and 100 000 T2D participants into our clustering model to investigate the trajectories of endotypes toward T2D complications.Results: The study population comprised 68% male participants, with a median age of 54 years, HbA1c of 6.9%, and BMI of 28.7 kg/m². Four endotypes were identified, differentiated by variations in CIC concentrations and specific plasma proteins. Two distinct endotypes, representing 19% and 24% of the cohort, demonstrated a higher progression toward cardiovascular outcomes, cardiovascular death, and nephropathy. Notably, one of these two endotypes exhibited a unique immune response driven predominantly by an enrichment of a subpopulation of classical monocytes, characterized by activation of the endoplasmic reticulum stress and mTOR pathways.Conclusion: Incorporating CIC numeration into a T2D endotyping algorithm refines the classification of T2D and identifies inflammatory endotypes. These “highly inflamed” T2D individuals exhibit an increased risk of diabetes-related complications.
B. Vuong: None. J. Julla: Other Relationship; Lilly Diabetes. Board Member; Sanofi. Other Relationship; Novo Nordisk. L. Potier: Consultant; AstraZeneca, Lilly Diabetes, Novo Nordisk, Bayer Pharmaceuticals, Inc, Sanofi. N. Venteclef: None. J. Gautier: Board Member; Sanofi. Advisory Panel; Pfizer Inc, Novo Nordisk. Other Relationship; Eli Lilly and Company.
Horizon Europe (101095433)
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