Genetic and Physiological Effects of Insulin on Human Urate Homeostasis
| Autor: | Tony R. Merriman, Megan Leask, Christopher Estiverne, Asim K. Mandal, David B. Mount, Hyon K. Choi |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway insulin receptor (INSR) medicine.medical_specialty insulin receptor substrate (IRS1) Physiology medicine.medical_treatment Urate homeostasis proximal tubule epithelial cell line (PTC-05) phosphoinositide 3-kinase (PI3K) Urate transport a urate transporter(GLUT9) 03 medical and health sciences 0302 clinical medicine Physiology (medical) Internal medicine medicine serum urate (SU) QP1-981 Hyperuricemia Protein kinase B Original Research 030203 arthritis & rheumatology biology Chemistry Insulin medicine.disease IRS1 glucose transporter-9 (GLUT9) Insulin receptor organic anion transporter (OAT) 030104 developmental biology Endocrinology biology.protein |
| Zdroj: | Frontiers in Physiology Frontiers in Physiology, Vol 12 (2021) |
| ISSN: | 1664-042X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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