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OBJECTIVE: To identify metabolic signatures of insulin action/secretion in Indigenous Americans (IAs) and their association with diabetes.RESEARCH DESIGN AND METHODS: We defined circulating metabolomic signatures of insulin action/secretion in 446 IAs, including glucose disposal rate during low-dose insulin clamp (Mlow) and endogenous glucose production (EGP) during insulin infusion (suppression of hepatic glucose production). We then determined associations of these metabolic scores with glucose tolerance (in a separate set of ∼700 IAs) and diabetes/metabolic risk in ∼2,000 individuals (from Coronary Artery Risk Development in Young Adults [CARDIA] study). We used tissue-specific gene-metabolite mapping to pinpoint genetic pathways of type 2 diabetes (T2D) implicated by metabolomic signatures.RESULTS: In young IAs (mean age 29 years; mean BMI 34.9 kg/m2) without diabetes, phenotype-metabolome associations across multiple insulin action phenotypes were linked to mechanisms of fatty acid and amino acid metabolism and inflammation (among others). Metabolite-based scores of insulin action were strongly related to incident diabetes in our discovery IA population (Mlow; 49 metabolites; standardized hazard ratio [HR] 0.49; 95% CI 0.35-0.69; P < 0.0001) and also associated with measures of insulin resistance in a distinct IA population (|ρ| ∼0.3-0.5 correlation) and in the CARDIA group (median age 33 years). At ∼20 years of follow-up in CARDIA, we observed a strong BMI- and glucose-independent association of the metabolite profile of Mlow (HR 0.65; 95% CI 0.56-0.74; P < 0.0001) and EGP suppression (HR 0.66; 95% CI 0.57-0.76; P < 0.0001) with incident diabetes, directionally opposed to BMI and glucose. Genes implicated by the metabolomic signatures were strongly linked to T2D.CONCLUSIONS: Metabolic signatures of clamp-determined insulin action are strongly associated with incident diabetes, suggesting causal-functional pathways of T2D.