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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月15日

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  • 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,
  • Alisa K. Manning

摘要

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.