Immunometabolic endotypes define distinct clinical trajectories in type 2 diabetes.
Abstract
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.