HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Heterogeneous effects on type 2 diabetes and cardiovascular outcomes of genetic variants and traits associated with fasting insulin.

Abstract
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.
AuthorsAlisa Manning, Magdalena Sevilla-González, Kirk Smith, Ningyuan Wang, Aubrey Jensen, Elizabeth Litkowski, Hyunkyung Kim, Daniel DiCorpo, Kenneth Westerman, Jinrui Cui, Ching-Ti Liu, Chenglong Yu, John McNeil, Paul Lacaze, Kyong-Mi Chang, Phil Tsao, Lawrence Phillips, Mark Goodarzi, Rob Sladek, Jerome Rotter, Josee Dupuis, Jose Florez, Jordi Merino, James Meigs, Jin Zhou, Sridharan Raghavan, Miriam Udler
JournalResearch square (Res Sq) (Sep 19 2023) United States
PMID37790568 (Publication Type: Preprint)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: