Insulin genetic clusters and clinical outcomes in Hispanics/Latinos

Increased fasting insulin reflects insulin resistance and is as a precursor to type 2 diabetes and a risk factor for kidney, heart and liver diseases and mortality. Cluster-specific fasting insulin polygenic scores (PS) characterize insulin resistance mechanisms based on insulin-related genetic associations with metabolic traits, and they have not been evaluated for liver outcomes. We calculated seven previously developed FI cluster-specific PS, including non-diabetogenic (Preserved Insulin Secretion, Elevated Insulin Secretion, Proinsulin) and diabetogenic clusters (Adiposity-driven Hyperinsulinemia, Visceral Adiposity, Lipodystrophy, Liver/Lipid) in 12,631 participants of the Hispanic Community Healthy Study/Study of Latinos (HCHS/SOL), and tested their association with type 2 diabetes, cardiovascular, kidney and liver outcomes. We also tested the association of FI clusters with indices of insulin homeostasis in additional 1,316 Hispanic individuals. Among HCHS/SOL participants (mean age 46 years, 59% women, 20% with diabetes), we validated associations of FI cluster-specific PS and the 19 traits used to generate clusters. The Lipodystrophy cluster was associated with type 2 diabetes (p-value =3.5 x 10 ^-5 ). In addition, the Adiposity-driven Hyperinsulinemia cluster was associated with the hepatic steatosis index (p-value = 2.2 ×10 ⁻¹⁷ ) and the fatty liver index (p-value = 1.7 ×10 ⁻¹⁴ ), while the Liver/Lipid cluster with liver fibrosis (p-value = 1.5 ×10 ⁻⁴ ) and lower kidney function (p-value = 5.2 x 10 ^-5 ). The non-diabetogenic Elevated Insulin Secretion cluster-specific PS was associated with the disposition index (p = 0.0015). These results support insulin resistance mechanisms implicated in type 2 diabetes, liver and kidney outcomes.