Mandal A.K., Mount D.B.
Affiliation(s):
Renal Divisions, Brigham and Women's Hospital and VA Boston
Background: Caffeine inhibits insulin signaling and has beneficial effects in metabolic syndrome/hyperinsulinemia. Coffee drinking also has beneficial effects in gout, via mechanisms unknown. We hypothesized that caffeine would specifically block insulin-activated urate transport, which in turn mediates the association between hyperinsulinemia and hyperuricemia.
Methods: We examined the effect of caffeine and adenosine on C-urate transport in absence and presence of insulin, on activation of insulin signaling pathways in human renal epithelial cell line (PTC-05), and on individual urate transporters expressed in Xenopus laevis oocytes.
Results: We found that both caffeine and adenosine inhibited both basal and insulin-stimulation of net Curate uptake in PTC-05 proximal tubular cells. In Xenopus laevis oocytes expressing individual urate transporters, caffeine efficiently inhibited the basal urate transport activity of GLUT9 isoforms, OAT4, OAT1, OAT3, NPT1, ABCG2 and ABCC4 at >0.2 mM; adenosine had weaker effects on basal urate transport. The IC-50 of caffeine for basal urate transport was 613 μM for GLUT9a, 1080 μM for GLUT9b, 145 μM for OAT1, 8 μM for murine OAT3, 582 μM for OAT10, and 4860 μM for URAT1. Caffeine at lower concentrations (<0.2 mM) very effectively inhibited insulin-activation of urate transport activity of GLUT9, OAT10, OAT1, OAT3, NPT1, ABCG2 and ABCC4, with concomitant inhibition of insulin-activated Akt and ERK phosphorylation. For example, the IC-50 of caffeine for insulin-activated GLUT9a urate transport was 205 μM. In contrast, adenosine had no effect on insulin-activated AKT and ERK phosphorylation.
Conclusion: Caffeine and adenosine inhibit basal urate transport mediated by multiple urate transporters. Caffeine also potently inhibits insulin-activated urate transport, with a significantly lower IC-50 for GLUT9a insulin-activated transport versus basal transport. To the extent that GLUT9a is postulated to be the major insulin-activated reabsorptive pathway for urate in the proximal tubule (Front Physiol. 2021 Aug 2;12:713710), caffeine potentially provides a unique in vivo probe for insulin-activated renal urate reabsorption. Additionally, these results provide an explanation for the beneficial effects of caffeine in gout, worthy of further exploration.