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

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 cardiov

SUBMITTER: Sevilla-Gonzalez M 

PROVIDER: S-EPMC11910595 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature