Divergent uric acid responses to a traditional Japanese diet and the DPP-4 inhibitor alogliptin in drug-naïve subjects with type 2 diabetes

Abstract Uric acid (UA) is traditionally regarded as a metabolic risk marker; however, its dynamic behavior during glucose-lowering therapy remains incompletely understood. We compared UA responses to a modified traditional Japanese diet (MJDD) and the DPP-4 inhibitor alogliptin in patients with early-stage type 2 diabetes mellitus (T2DM). In this prospective observational study, drug-naïve patients received MJDD (n=58) or alogliptin (n=52) monotherapy for 3 months. Changes (Δ) in serum UA were analyzed in relation to glycemic control, insulin resistance, adipose tissue insulin resistance (adipo-IR), and beta-cell function. Both interventions significantly reduced fasting blood glucose and HbA1c while paradoxically increasing serum UA and HOMA-B. Baseline UA was the primary determinant of ΔUA in both cohorts. MJDD significantly reduced body mass index, insulin, free fatty acids, HOMA-R, and adipo-IR, with effects most pronounced in subjects with baseline BMI >25. In contrast, alogliptin selectively reduced adipo-IR in leaner subjects (BMI <25). Across both treatments, ΔUA correlated positively with ΔHOMA-B and inversely with ΔHbA1c. Notably, during MJDD, ΔUA showed a paradoxical negative correlation with ΔBMI and ΔFBG, and a positive correlation with ΔFFA. Patients exhibiting the greatest UA increases demonstrated the most marked improvements in beta-cell function and, with MJDD, the greatest weight loss. These findings indicate that MJDD and alogliptin exert distinct metabolic effects in early T2DM, yet both link rising UA to enhanced beta-cell function, suggesting that UA may serve as a dynamic pharmacometabolic biomarker reflecting therapy-specific metabolic adaptation rather than metabolic deterioration.