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Abstract: TH-PO484

Insulin: Genetic and Physiological Influences on Human Uric Acid Homeostasis

Session Information

Category: Fluid and Electrolytes

  • 901 Fluid and Electrolytes: Basic

Authors

  • Mount, David B., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Merriman, Tony, University of Otago, Dunedin, New Zealand
  • Mandal, Asim, Brigham and Women's Hospital, Boston, Massachusetts, United States
Background

Insulin plays a key role in hyperuricemia. In particular, hyperinsulinemia in metabolic syndrome is inversely correlated with urinary uric acid (UA) excretion and insulin infusion in humans reduces urinary fractional excretion of UA.

Methods

An existing GWAS cohort was analyzed, testing for association between genetic variants in the insulin and insulin receptor genes with serum UA (SUA). HEK 293T cells, human PTC5 proximal tubule cells, and Xenopus oocytes were probed with antibodies to UA transporters, the insulin receptor, downstream kinases, and the relevant phospho-kinases. 14C-UA transport was assayed in these cell lines and in oocytes expressing individual transporters.

Results

Variants in the human insulin and insulin receptor genes demonstrated significance for association with variation in SUA, at p<10-4 and p<10-7, respectively. HEK293T and PTC5 proximal tubular cells express several endogenous UA transporter proteins, including GLUT9, OAT10, and URAT1. Insulin activates PI3 kinase/Akt and MEK/ERK signaling pathways through the insulin receptor in HEK 293T and PTC5 cells, as detected with phospho-kinase antibodies, with activation of endogenous 14C-UA transport. The stimulatory effect of insulin on UA uptake is abrogated by uricosurics and by inhibition of protein tyrosine kinase (genistein), PI3 kinase (LY295002), and MEK/ERK (PD98059). UA transport mediated by GLUT9a, GLUT9b, OAT10, OAT3, OAT1, NPT1 and ABCG2, expressed separately in Xenopus oocytes, is also activated by insulin, with equivalent activation of signaling pathways and differential effects of signaling inhibitors on insulin-stimulated UA transport. Insulin has no effect on URAT1, OAT4, and the SMCT1/2 nicotinate transporters, when expressed in oocytes. GLUT9a is the basolateral exit pathway in reabsorption of filtered UA by the proximal tubule; given much greater absolute UA transport rates mediated by GLUT9 isoforms, much of the anti-uricosuric effect of in vivo insulin infusion is likely due to activation of GLUT9a.

Conclusion

Variation in the human insulin and insulin receptor genes affects SUA. Insulin and associated signaling pathways also activate multiple UA transporters, indicating a pivotal physiological role for insulin in UA homeostasis. We postulate that basolateral GLUT9a in the proximal tubule is the dominant post-translational target of insulin in the regulation of renal UA transport.

Funding

  • Other NIH Support