Gene-environment interaction modifies the association between hyperinsulinemia and serum urate levels through SLC22A12.
Level 3 - non-randomized controlled study
Non-randomized cross-sectional cohort and large observational biobank analysis coupled with in vitro mechanistic assays
PubMed 40100301 · doi:10.1172/JCI186633
What was done
The authors examined the relationship between hyperinsulinemia and renal fractional excretion of urate (FEUA) in a clinical cohort of 162 outpatients. They evaluated downstream molecular mechanisms using kinase screening, single-cell data analysis, and cell culture experiments assessing urate transporter 1 (URAT1, encoded by SLC22A12) phosphorylation and transport activity. They further analyzed observational associations and gene-environment interactions involving serum urate, hyperinsulinemia, salt intake, and the SLC22A12 expression quantitative trait locus (eQTL) rs475688 across 377,358 UK Biobank participants.
What was found
The index of hyperinsulinemia was inversely associated with FEUA independently of covariates (no effect sizes reported in the abstract). Mechanistically, AKT (stimulated by hyperinsulinemia) and SGK1 (induced by high salt) phosphorylated URAT1 at Thr408, requiring Arg405, which increased URAT1 cell-surface abundance and urate transport activity. In 377,358 UK Biobank participants, hyperinsulinemia and high salt intake were independently associated with higher serum urate levels. The SLC22A12 eQTL rs475688 synergistically enhanced the positive association between hyperinsulinemia and serum urate (no numerical estimates or p-values provided in the abstract).
Why it matters
This study identifies a direct molecular mechanism linking hyperinsulinemia and high salt intake to reduced urate excretion via URAT1 phosphorylation. It demonstrates how genetic variation in SLC22A12 interacts with metabolic and dietary factors to elevate serum urate, pointing toward personalized targets for hyperuricemia management.
Limits
The abstract reports no numerical effect sizes, confidence intervals, or p-values. The human studies are observational and cross-sectional, precluding causal certainty. The outpatient sample was small (n = 162), and transport mechanisms were primarily characterized in cell culture models rather than in vivo human tissue.
Cited by
- supports There is a feed-forward cycle between insulin and uric acid clearance in the kidneys.