MON-629 Insulin Resistance, Hyperinsulinemia, And Uric Acid: Mechanistic Insights From Rare Disorders

Abstract Disclosure: R. Kesharaju: None. A. Deven: None. R. Jain: None. A. Rabel: None. R. Muniyappa: None. Background: Uric acid (UA), the final product of purine catabolism, is implicated in gout and metabolic syndrome, frequently co-occurring with obesity, hypertension, and dyslipidemia. Both hyperinsulinemia and insulin resistance have been mechanistically linked to elevated UA, but the individual contributions of each remain unclear. Understanding how insulin action affects UA metabolism may clarify the pathophysiology of hyperuricemia in cardiometabolic disease. Objective and Methods: This study examined whether hyperinsulinemia alone or in combination with insulin resistance influences plasma UA levels by analyzing four participant groups: lean/overweight (n=37, age 41.8 ± 15.04 years, BMI 25.1 ± 2.7 kg/m2), obese (n=49, age 45.8 ± 12.4 years, BMI 38.6 ± 6.3 kg/m2), insulinoma (n=53, age 49.6 ± 14.5 years, BMI 29.8 ± 6.6 kg/m2), and insulin receptor mutation carriers (n=15, age 23.7 ± 13.5 years, BMI 20.1 ± 6.0 kg/m2). In lean, overweight, and obese participants, insulin sensitivity (SI) was assessed via a frequently sampled intravenous glucose tolerance test using the minimal model, while plasma UA levels and fractional excretion were measured to evaluate their association with insulin parameters. Results: SI was positively correlated with fractional UA excretion and inversely associated with plasma UA levels. Fasting insulin levels were lowest in lean/overweight individuals, higher in obese participants, markedly elevated among those with insulinoma, and highest in patients harboring receptor mutations. Plasma UA levels were significantly higher in obese participants compared to both lean/overweight controls (5.5±1.4 vs. 4.5±1.0 mg/dL) and individuals with insulinoma (4.6±0.9 mg/dL). Despite the highest insulin levels and complete insulin resistance, individuals with near-complete receptor defects had the lowest UA (3.1±1.3 mg/dL, p<0.0001 vs. obese), suggesting that hyperinsulinemia alone is insufficient to raise UA and that partial or post-receptor insulin resistance is required for marked hyperuricemia. Conclusion: Total loss of insulin signaling results in lower uric acid levels, even in the presence of extreme hyperinsulinemia. Our results suggest that hyperinsulinemia and partial or post-receptor insulin resistance are necessary to drive higher plasma uric acid levels, as observed in obesity. Presentation: Monday, July 14, 2025