{"doi":"10.2337/dc25-0151","title":"Human Physiologic Responses to Insulin in Indigenous Americans Identify a Metabolic Susceptibility Profile Linked to Diabetes","abstract":"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.","journal":"Diabetes Care","year":2025,"id":533742,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9443,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":260537,"name":"Paolo Piaggi","orcid":"0000-0003-2774-9161","position":1,"is_corresponding":false},{"id":1056047,"name":"Phillip Lin","orcid":"0009-0003-6988-0237","position":2,"is_corresponding":false},{"id":298186,"name":"Shilin Zhao","orcid":"0000-0002-3921-3965","position":3,"is_corresponding":false},{"id":236708,"name":"Lindsey K. Stolze","orcid":"0000-0003-2269-769X","position":4,"is_corresponding":false},{"id":801152,"name":"Andrew Perry","orcid":"0000-0003-3342-6158","position":5,"is_corresponding":false},{"id":439831,"name":"Robert L. Hanson","orcid":"0000-0002-4252-7068","position":6,"is_corresponding":false},{"id":262998,"name":"J. Jeffrey Carr","orcid":"0000-0002-4398-8237","position":7,"is_corresponding":false},{"id":374283,"name":"James G. Terry","orcid":"0000-0001-6659-3441","position":8,"is_corresponding":false},{"id":439829,"name":"Leslie J. Baier","orcid":"0000-0002-8773-9670","position":9,"is_corresponding":false},{"id":522447,"name":"Clifton Bogardus","orcid":"0000-0003-1472-3376","position":10,"is_corresponding":false},{"id":6946,"name":"Clary B. Clish","orcid":"0000-0001-8259-9245","position":11,"is_corresponding":false},{"id":15605,"name":"Eric R. Gamazon","orcid":"0000-0003-4204-8734","position":12,"is_corresponding":false},{"id":260540,"name":"Jonathan Krakoff","orcid":"0000-0001-6074-5600","position":13,"is_corresponding":false},{"id":251876,"name":"Ravi V. Shah","orcid":"0000-0002-4471-7156","position":14,"is_corresponding":false},{"id":326582,"name":"Venkatesh L. Murthy","orcid":"0000-0002-7901-1321","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:51:43.451278Z","pmid":"40392570","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}