Human physiologic responses to insulin in Indigenous Americans identify a metabolic susceptibility profile linked to diabetes

Objective: To identify a metabolic signature of insulin action/secretion in Indigenous Americans (IAs) and its 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 during insulin infusion (“HGP” suppression). We related these metabolic scores to glucose tolerance (in a separate set of ≈700 IAs) and to diabetes/metabolic risk in≈2000 individuals (CARDIA). 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; BMI 34.9 kg/m2) without diabetes, phenotype-metabolome relations 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 HR = 0.49, 95% CI 0.35-0.69, P<0.0001) and were also associated with measures of insulin resistance in a distinct IA population (||≈0.3-0.5 correlation) and in CARDIA (median age 33 years). At ≈20 years 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 or 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, specifying causal-functional pathways of T2D.