THU268 Hyperuricemia In Insulin Resistance Is Associated With Increased Synthesis And Not Decreased Renal Excretion Of Uric Acid In Humans

Disclosure: R. Haykal: None. A. Kinzer: None. B. Abel: None. M. Lightbourne: None. M.S. Startzell: None. E. Cochran: None. R.J. Brown: None. Title: Hyperuricemia in insulin resistance is associated with increased synthesis and not decreased renal excretion of uric acid in humans. Background: In obesity and lipodystrophy (LD), insulin resistance (IR) is “selective”, with lack of insulin signaling causing hyperglycemia, but enhanced insulin signaling causing dyslipidemia. Rare human conditions exist in which there is extreme, non-selective IR impairing all insulin signaling pathways (e.g. mutations of the insulin receptor, INSR), resulting in hyperglycemia without dyslipidemia. We previously found that patients with non-selective IR do not have the hyperuricemia observed in selective IR. Potential mechanisms of hyperuricemia in selective IR include altered expression of renal uric acid transporters leading to impaired uric acid excretion, and increased activity of xanthine oxidoreductase (XOR), causing increased uric acid synthesis. We thus hypothesized that enhanced insulin signaling in selective IR would result in decreased fractional excretion of uric acid (FEUA) and/or increased biomarkers of XOR activity compared to non-selective IR. Method: We conducted 2 cross-sectional analyses of patients with severe IR that was either selective (due to LD) or non-selective (due to INSR mutation). Analysis 1 compared fasting insulin, fasting serum uric acid, and FEUA from 24-hr urine collection in 46 patients with LD and 13 with INSR. Analysis 2 compared products of purine nucleotide catabolism and salvage pathways by untargeted metabolomics in serum of 30 subjects each with LD and INSR. Results: In analysis 1, fasting insulin was lower in LD vs INSR (median 37.5 [25th-75th percentile 23.1-87.0] vs 88.7 [41.9-458.6] mcU/mL; P=0.0097). Serum uric acid was higher in LD vs INSR (5.3±1.6 vs 3.3±1.0 mg/dL; P=0.04). FEUA was comparable in the 2 groups (9.0±5 vs 8.5±3.5%; P=0.75). In analysis 2, uric acid was 1.6 fold higher (P