Bao Tran Vuong, Chloé M Delépine, Jacqueline M Ratter-Rieck, Elisabetta Rinaldi, Jean-Baptiste Julla, Emma Creussot, Marc Diedisheim, Violeta Raverdy, Elise Liu, Justus S Fischer, Matthias Hepprich, Fawaz Alzaid, Camille Blériot, Etienne Becht, Clémence Cornuot, Joe de Keizer, Macine-Bachir Abdelouahab, Magali Chiral, Rebecca Pfeil, Polina Lipaeva, Daniel Dörr, Oana P Zaharia, Théo Jolivet, Julie Alberge, Charline Potier, Kennan Khider, Frédérik Oger, Jean-Pierre Riveline, Tiphaine Vidal-Trecan, Florence Tubach, Candice Estellat, Judith Abecassis, Aymeric Silvin, Samy Hadjadj, Gael Varoquaux, Robert Wagner, Philippe Froguel, Amélie Bonnefond, Pierre-Jean Saulnier, François Pattou, Florent Ginhoux, Michael Roden, Maddalena Trombetta, Louis Potier, Christian Herder, Jean-François Gautier, Marc Y Donath, Riccardo C Bonadonna, Nicolas Venteclef
Type 2 diabetes (T2D) is a heterogeneous disease, yet current classifications do not capture its clinico-biological complexity or support precision-based care. We developed an endotyping strategy based on routine blood immune cell counts across more than 1,500 individuals with newly diagnosed T2D from three European cohorts. Unsupervised clustering identified four reproducible immune endotypes: severe inflammatory diabetes (SIND), mild inflammatory diabetes (MIND), lymphocyte-rich diabetes (LYRD), and lymphocyte-deficient diabetes (LYDD). Endotypes were stable, robust to de novo clustering, and independent of age, sex, BMI, and HbA1c. SIND and LYDD were associated with increased cardiovascular, renal, and mortality risk across cohorts. Immune endotyping improved cardiovascular risk prediction beyond SCORE2-Diabetes. Multi-omic profiling revealed immunopathological states, with high-risk endotypes characterized by monocyte-driven inflammation and dysregulated lymphocyte programs. The inflammatory profile of SIND was attenuated by IL-1β antagonism and bariatric surgery. These findings establish immune endotyping as a scalable framework for immunometabolic risk stratification in T2D.