Background and Aim: The contribution of gut‐derived factors to the mechanisms linking obesity and metabolic disease remains under‐investigated. The aim of the current study was to examine the associations between glucagon and enteroendocrine signaling and type 2 diabetes (T2D) using a derived risk score approach. To compare the relative importance of the enteroendocrine system, associations between adipokine measures and T2D were also investigated. Methods: A total of 130 individuals with T2D and 161 individuals without T2D were included in the study. Circulating concentrations of enteroendocrine (glucagon, ghrelin, glucagon‐like peptide‐1, and gastric inhibitory peptide) and adipokine mediators (adiponectin, leptin, resistin, visfatin, and adipsin) were measured. Standard scores (Z‐scores) were determined for each measure and enteroendocrine risk scores (ERS) and adipokine risk scores (ARS) calculated based on summation of the component measures. Associations between both the ERS and ARS and T2D status were assessed using logistic regression models. Results: The ERS was significantly associated with T2D status in an adjusted model (odds ratio: 1.36; 95% confidence interval [CI]: 1.08–1.72; P = 0.009). Associations between the ARS and T2D status were not independent of age, sex, and body mass index (odds ratio: 1.21; 95%CI: 0.99–1.47; P = 0.06). Quantification of risk across ERS tertiles revealed that individuals with an ERS in the upper tertile were 10 times more likely (CI: 3.23–32.73; P < 0.001) to have T2D. Conclusions: These data support an association between enteroendocrine signaling and T2D. Use of the ERS as a potential tool for classifying individuals with metabolic syndrome as high or low risk for T2D development is being considered.