Human Physiologic Responses to Insulin in Indigenous Americans Identify a Metabolic Susceptibility Profile Linked to Diabetes
Authors' conclusion
Metabolic signatures of clamp-determined insulin action are strongly associated with incident diabetes, suggesting causal-functional pathways of T2D.
Study context
- Population
- Indigenous Americans without diabetes (young; mean age 29 years; mean BMI 34.9 kg/m²) with insulin clamp; validation in a separate IA set (∼700) and CARDIA (∼2,000; median age 33 years)discovery IA cohort
- Participants
- 446 participants
- Outcome
- Association of metabolite-based scores of insulin action/secretion (Mlow, EGP suppression) with incident diabetes
Methodological detailsdiscovery and validation cohorts, tissue-specific gene-metabolite mapping
- Discovery and validation cohorts
- Tissue-specific gene-metabolite mapping
Main finding
As reported in the abstract
Incident diabetes per metabolite score of Mlow (49 metabolites), discovery IA population
Standardized HR
0.49
95% CI 0.35–0.69P < 0.0001
Observational data: associations, not effects.
Further findings
Incident diabetes in CARDIA, BMI- and glucose-independent · ∼20 years of follow-up
- Metabolite profile of Mlow: HR
- 0.65 (95% CI 0.56-0.74; P < 0.0001)
- Metabolite profile of endogenous glucose production (EGP) suppression: HR
- 0.66 (95% CI 0.57-0.76; P < 0.0001)
- Directionally opposed to BMI and glucose
Correlation with measures of insulin resistance in a distinct IA population
- |ρ|
- ∼0.3-0.5
Genes implicated by metabolomic signatures
- Strongly linked to T2D
Original publication
Human Physiologic Responses to Insulin in Indigenous Americans Identify a Metabolic Susceptibility Profile Linked to Diabetes. Diabetes Care. Published 20 May 2025. doi:10.
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