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Front Physiol 2021 Jan 01;12:713710. doi: 10.3389/fphys.2021.713710.
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Genetic and Physiological Effects of Insulin on Human Urate Homeostasis.

Mandal AK , Leask MP , Estiverne C , Choi HK , Merriman TR , Mount DB .

Insulin and hyperinsulinemia reduce renal fractional excretion of urate (FeU) and play a key role in the genesis of hyperuricemia and gout, via uncharacterized mechanisms. To explore this association further we studied the effects of genetic variation in insulin-associated pathways on serum urate (SU) levels and the physiological effects of insulin on urate transporters. We found that urate-associated variants in the human insulin (INS), insulin receptor (INSR), and insulin receptor substrate-1 (IRS1) loci associate with the expression of the insulin-like growth factor 2, IRS1, INSR, and ZNF358 genes; additionally, we found genetic interaction between SLC2A9 and the three loci, most evident in women. We also found that insulin stimulates the expression of GLUT9 and increases [14C]-urate uptake in human proximal tubular cells (PTC-05) and HEK293T cells, transport activity that was effectively abrogated by uricosurics or inhibitors of protein tyrosine kinase (PTK), PI3 kinase, MEK/ERK, or p38 MAPK. Heterologous expression of individual urate transporters in Xenopus oocytes revealed that the [14C]-urate transport activities of GLUT9a, GLUT9b, OAT10, OAT3, OAT1, NPT1 and ABCG2 are directly activated by insulin signaling, through PI3 kinase (PI3K)/Akt, MEK/ERK and/or p38 MAPK. Given that the high-capacity urate transporter GLUT9a is the exclusive basolateral exit pathway for reabsorbed urate from the renal proximal tubule into the blood, that insulin stimulates both GLUT9 expression and urate transport activity more than other urate transporters, and that SLC2A9 shows genetic interaction with urate-associated insulin-signaling loci, we postulate that the anti-uricosuric effect of insulin is primarily due to the enhanced expression and activation of GLUT9.

PubMed ID: 34408667
PMC ID: PMC8366499
Article link: Front Physiol

Species referenced: Xenopus laevis
Genes referenced: abcc4 abcg2 grap2 igf2 ins insr irs1 kcnk3 mapk1 mapk14 pik3cg ptk2b slc13a3 slc22a13 slc22a6 slc2a9 slc5a8
GO keywords: urate transport [+]

Disease Ontology terms: gout [+]

Article Images: [+] show captions
References [+] :
Almind, A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. 1996, Pubmed