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

• Published in: Nature communications Vol. 16; no. 1; pp. 2569 - 12
• Main Authors: Sevilla-González, Magdalena, Smith, Kirk, Wang, Ningyuan, Jensen, Aubrey E., Litkowski, Elizabeth M., Kim, Hyunkyung, DiCorpo, Daniel A., Hsu, Sarah, Cui, Jinrui, Liu, Ching-Ti, Yu, Chenglong, McNeil, John J., Lacaze, Paul, Westerman, Kenneth E., Chang, Kyong-Mi, Tsao, Philip S., Phillips, Lawrence S., Goodarzi, Mark O., Sladek, Rob, Rotter, Jerome I., Dupuis, Josée, Florez, Jose C., Merino, Jordi, Meigs, James B., Zhou, Jin J., Raghavan, Sridharan, Udler, Miriam S., Manning, Alisa K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.03.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 692/308/174; 692/499; 692/699/2743/2815; Adipose tissue; Adult; Body fat; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - blood; Cardiovascular Diseases - genetics; Cerebral infarction; Clusters; Coronary artery disease; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Fasting; Fasting - blood; Female; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genetic Variation; Health risks; Heart diseases; Humanities and Social Sciences; Humans; Hyperinsulinemia; Hyperinsulinism - blood; Hyperinsulinism - genetics; Insulin; Insulin - blood; Insulin - metabolism; Insulin secretion; Lipids; Male; Middle Aged; multidisciplinary; Myocardial infarction; Myocardial Infarction - genetics; Polygenic inheritance; Polymorphism, Single Nucleotide; Risk; Science; Science (multidisciplinary); Similarity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-025-57452-y

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. Here, the authors implement a genetic approach grouping fasting insulin-associated genetic variants based on their genetic and phenotypic similarities and highlight specific processes that decouple increased fasting insulin levels from T2D and cardiovascular risk, offering potential avenues for investigating process-specific pathways of disease risk.