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

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. McNeil, Paul Lacaze, Kenneth E. Westerman, Kyong-Mi Chang, Philip S. Tsao, Lawrence S. Phillips, Mark O. Goodarzi, Rob Sladek, Jerome I. Rotter, Josée Dupuis, Jose C. Florez, Jordi Merino, James B. Meigs, Jin J. Zhou, Sridharan Raghavan, Miriam S. Udler () and Alisa K. Manning ()
Additional contact information
Magdalena Sevilla-González: Massachusetts General Hospital
Kirk Smith: The Broad Institute of MIT and Harvard
Ningyuan Wang: Boston University School of Public Health
Aubrey E. Jensen: Phoenix Veterans Affairs Medical Center
Elizabeth M. Litkowski: Veterans Affairs Eastern Colorado Health Care System
Hyunkyung Kim: The Broad Institute of MIT and Harvard
Daniel A. DiCorpo: Boston University School of Public Health
Sarah Hsu: The Broad Institute of MIT and Harvard
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
Kyong-Mi Chang: Corporal Michael J Crescenz VA Medical Center
Philip S. Tsao: Veterans Affairs Palo Alto Health Care System
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
Jose C. Florez: Harvard Medical School
Jordi Merino: The Broad Institute of MIT and Harvard
James B. Meigs: Harvard Medical School
Jin J. Zhou: Phoenix Veterans Affairs Medical Center
Sridharan Raghavan: Veterans Affairs Eastern Colorado Health Care System
Miriam S. Udler: Harvard Medical School
Alisa K. Manning: Massachusetts General Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57452-y

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