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Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes

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Listed:
  • Magdalena Sevilla-González

    (Massachusetts General Hospital
    Harvard Medical School
    The Broad Institute of MIT and Harvard)

  • Kirk Smith

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Ningyuan Wang

    (Boston University School of Public Health)

  • Aubrey E. Jensen

    (Phoenix Veterans Affairs Medical Center
    UCLA Fielding School of Public Health)

  • Elizabeth M. Litkowski

    (Veterans Affairs Eastern Colorado Health Care System
    University of Colorado Anschutz Medical Campus)

  • Hyunkyung Kim

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Daniel A. DiCorpo

    (Boston University School of Public Health)

  • Sarah Hsu

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Jinrui Cui

    (Cedars-Sinai Medical Center)

  • Ching-Ti Liu

    (Boston University School of Public Health)

  • Chenglong Yu

    (Monash University)

  • John J. McNeil

    (Monash University)

  • Paul Lacaze

    (Monash University)

  • Kenneth E. Westerman

    (Massachusetts General Hospital
    Harvard Medical School
    The Broad Institute of MIT and Harvard)

  • Kyong-Mi Chang

    (Corporal Michael J Crescenz VA Medical Center
    University of Pennsylvania Perelman School of Medicine)

  • Philip S. Tsao

    (Veterans Affairs Palo Alto Health Care System
    Stanford University School of Medicine)

  • Lawrence S. Phillips

    (Atlanta VA Medical Center)

  • Mark O. Goodarzi

    (Cedars-Sinai Medical Center)

  • Rob Sladek

    (McGill University)

  • Jerome I. Rotter

    (The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center)

  • Josée Dupuis

    (Boston University School of Public Health
    McGill University)

  • Jose C. Florez

    (Harvard Medical School
    The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Jordi Merino

    (The Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    University of Copenhagen)

  • James B. Meigs

    (Harvard Medical School
    The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Jin J. Zhou

    (Phoenix Veterans Affairs Medical Center
    UCLA Fielding School of Public Health)

  • Sridharan Raghavan

    (Veterans Affairs Eastern Colorado Health Care System
    University of Colorado Anschutz Medical Campus)

  • Miriam S. Udler

    (Harvard Medical School
    The Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Alisa K. Manning

    (Massachusetts General Hospital
    Harvard Medical School
    The Broad Institute of MIT and Harvard)

Abstract

Elevated fasting insulin levels (FI), indicative of altered insulin secretion and sensitivity, may precede type 2 diabetes (T2D) and cardiovascular disease onset. In this study, we group FI-associated genetic variants based on their genetic and phenotypic similarities and identify seven clusters with distinct mechanisms contributing to elevated FI levels. Clusters fall into two types: “non-diabetogenic hyperinsulinemia,” where clusters are not associated with increased T2D risk, and “diabetogenic hyperinsulinemia,” where T2D associations are driven by body fat distribution, liver function, circulating lipids, or inflammation. In over 1.1 million multi-ancestry individuals, we demonstrated that diabetogenic hyperinsulinemia cluster-specific polygenic scores exhibit varying risks for cardiovascular conditions, including coronary artery disease, myocardial infarction (MI), and stroke. Notably, the visceral adiposity cluster shows sex-specific effects for MI risk in males without T2D. This study underscores processes that decouple elevated FI levels from T2D and cardiovascular risk, offering new avenues for investigating process-specific pathways of disease.

Suggested Citation

  • Magdalena Sevilla-González & Kirk Smith & Ningyuan Wang & Aubrey E. Jensen & Elizabeth M. Litkowski & Hyunkyung Kim & Daniel A. DiCorpo & Sarah Hsu & Jinrui Cui & Ching-Ti Liu & Chenglong Yu & John J., 2025. "Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57452-y
    DOI: 10.1038/s41467-025-57452-y
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