Hyperinsulinemia is a complex and heterogeneous phenotype that characterizes molecular alterations that precede the development of
type 2 diabetes (T2D). It results from a complex combination of molecular processes, including insulin secretion and
insulin sensitivity, that differ between individuals. To better understand the physiology of
hyperinsulinemia and ultimately T2D, we implemented a genetic approach grouping fasting
insulin (FI)-associated genetic variants based on their molecular and phenotypic similarities. We identified seven distinctive genetic clusters representing different physiologic mechanisms leading to rising FI levels, ranging from clusters of variants with effects on increased FI, but without increased risk of T2D (non-diabetogenic
hyperinsulinemia), to clusters of variants that increase FI and T2D risk with demonstrated strong effects on body fat distribution, liver,
lipid, and inflammatory processes (diabetogenic
hyperinsulinemia). We generated cluster-specific polygenic scores in 1,104,258 individuals from five multi-ancestry cohorts to show that the clusters differed in associations with cardiometabolic traits. Among clusters characterized by non-diabetogenic
hyperinsulinemia, there was both increased and decreased risk of
coronary artery disease despite the non-increased risk of T2D. Similarly, the clusters characterized by diabetogenic
hyperinsulinemia were associated with an increased risk of T2D, yet had differing risks of cardiovascular conditions, including
coronary artery disease,
myocardial infarction, and
stroke. The strongest cluster-T2D associations were observed with the same direction of effect in non-Hispanic Black, Hispanic, non-Hispanic White, and non-Hispanic East Asian populations. These genetic clusters provide important insights into granular metabolic processes underlying the physiology of
hyperinsulinemia, notably highlighting specific processes that decouple increasing FI levels from T2D and cardiovascular risk. Our findings suggest that increasing FI levels are not invariably associated with adverse cardiometabolic outcomes.