Background/Purpose: Insulin plays a key role in the genesis of hyperuricemia. In particular, hyperinsulinemia in metabolic syndrome is inversely correlated with urinary uric acid (UA) excretion and insulin infusion in humans also 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 human 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 phosphokinase
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,
when 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 in oocytes, 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/insulin-genetic-and-physiological-influences-on-human-uric-acid-homeostasis/