Genetic and Physiological Effects of Insulin on Human Urate Homeostasis

Abstract

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.

Biomarkers Predictive of Metabolic Syndrome and Cardiovascular Disease in Childhood Cancer Survivors

“…In studies carried out on mice, insulin acts at the renal level favoring the expression of the uric acid reabsorption system and decreasing the expression of a major urate secretory transporter [ 77 ]. In humans, it was widely demonstrated that insulin values correlate with uric acid values and reduce urinary excretion of uric acid, although the mechanism underlying this phenomenon is not fully known [ 78 , 79 , 80 ]. The excessive concentration of uric acid in the cells causes an increase in the activity of xanthine oxidase and causes damage to the mitochondria with a consequent increase in the production of reactive oxygen species [ 81 ].…”

Susceptibility genes of hyperuricemia and gout

“…2 ) [ 54 ]. Insulin can selectively activate its UA transport function [ 55 ]. Bahn et al [ 54 ] found that the expression of SLC22A13 in chickens was gender dependent, and the female was higher than the male.…”

“…Therefore, SLC2A9 SNPs may have a protective effect on gout, but its severe hypouricemia and its complications may endanger the lives of patients. Non-additive genetic interaction between SLC2A9 and insulin related genes also affects SUA [ 55 ]. Moreover, this effect is most obvious in women, which is consistent with the greater effect of SLC2A9 on UA in women.…”

“…Moreover, this effect is most obvious in women, which is consistent with the greater effect of SLC2A9 on UA in women. Insulin promotes the activity of various UA transporters via activating MAPK p38, MAPK p44/42 and Akt pathways [ 55 ]. E4 promoter- binding protein 4 ( E4BP4 ) gene directly binds P2 promoter to down-regulate the expression of SLC2A9 in mouse liver [ 64 ].…”

“…Furthermore, rs2231142 has gene dose effect on gout [ 61 ]. In Xenopus oocytes, insulin could up-regulate the transport activity of ABCG2, but does not affect the transport activity of Q141K variant [ 55 ]. In the mouse model, knock-in ABCG2 Q141K variant could down-regulate the expression of ABCG2 in male mice without affecting female mice [ 69 ].…”