Insulin genetic clusters and clinical outcomes in Hispanics/Latinos
- 1The University of North Carolina at Chapel Hill
Abstract
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 x1017) and the fatty liver index (p-value = 1.7 x1014), while the Liver/Lipid cluster with liver fibrosis (p-value = 1.5 x104) 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.
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BibTeX
@misc{reynolds2026insulin,
title = {{Insulin genetic clusters and clinical outcomes in Hispanics/Latinos}},
author = {K. M. Reynolds and J. Lash and A. Morris and M. L. Daviglus and L. C. Gallo and K. D. Taylor and J. Cai and J. Cui and H. Mattix-Kramer and Y.-D. I. Chen and D. Sotres-Alvarez and J. I. I. Rotter and M. O. Goodarzi and N. Franceschini},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.26367229},
url = {https://www.medrxiv.org/content/10.64898/2026.11.03.26367229v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Insulin genetic clusters and clinical outcomes in Hispanics/Latinos
AU - K. M. Reynolds
AU - J. Lash
AU - A. Morris
AU - M. L. Daviglus
AU - L. C. Gallo
AU - K. D. Taylor
AU - J. Cai
AU - J. Cui
AU - H. Mattix-Kramer
AU - Y.-D. I. Chen
AU - D. Sotres-Alvarez
AU - J. I. I. Rotter
AU - M. O. Goodarzi
AU - N. Franceschini
PY - 2026
DA - 2026/11/03
PB - medRxiv
DO - 10.64898/2026.11.03.26367229
UR - https://www.medrxiv.org/content/10.64898/2026.11.03.26367229v1
AB - 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 x1017) and the fatty liver index (p-value = 1.7 x1014), while the Liver/Lipid cluster with liver fibrosis (p-value = 1.5 x104) 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.
ER -