BACKGROUND: The inverse association between coffee consumption and the risk of type 2 diabetes (T2D) is well established; however, little is known about potential mediators of this association.OBJECTIVE: We aimed to investigate the association between coffee consumption and diabetes-related biomarkers and their potential role as mediators of the association between coffee consumption and T2D.DESIGN: We analyzed a case-cohort study (subcohort: n = 1610; verified incident T2D cases: n = 417) nested within the European Prospective Investigation into Cancer and Nutrition-Potsdam study involving 27,548 middle-aged participants. Habitual coffee consumption was assessed with a validated, semiquantitative food-frequency questionnaire. We evaluated the association between coffee consumption and several T2D-related biomarkers, such as liver markers (reflected by γ-glutamyltransferase, fetuin-A, and sex hormone-binding globulin), markers of dyslipidemia (high-density lipoprotein cholesterol and triglycerides), inflammation [C-reactive protein (CRP)], an adipokine (adiponectin), and metabolites, stratified by sex.RESULTS: Coffee consumption was inversely associated with diacyl-phosphatidylcholine C32:1 in both sexes and with phenylalanine in men, as well as positively associated with acyl-alkyl-phosphatidylcholines C34:3, C40:6, and C42:5 in women. Furthermore, coffee consumption was inversely associated with fetuin-A (P-trend = 0.06) and CRP in women and γ-glutamyltransferase and triglycerides in men. Coffee consumption tended to be inversely associated with T2D risk in both sexes, reaching significance only in men [HR (95% CI): women: ≥4 compared with >0 to 0 to