Genetic and Physiological Effects of Insulin-Like Growth Factor-1 (IGF-1) on Human Urate Homeostasis

Abstract

Background Metabolic syndrome and hyperinsulinemia are associated with hyperuricemia. Insulin infusion in healthy volunteers elevates serum urate (SU) by activating net urate reabsorption in the renal proximal tubule, whereas IGF-1 infusion reduces SU by mechanisms unknown. Variation within the IGF1R gene also affects SU levels.Methods Colocalization analyses of a SU genome-wide association studies signal at IGF1R and expression quantitative trait loci signals in cis using COLOC2, RT-PCR, Western blotting, and urate transport assays in transfected HEK 293T cells and in Xenopus laevis oocytes.Results Genetic association at IGF1R with SU is stronger in women and is mediated by control of IGF1R expression. Inheritance of the urate-lowering homozygous genotype at the SLC2A9 locus is associated with a differential effect of IGF1R genotype between men and women. IGF-1, through IGF-1R, stimulated urate uptake in human renal proximal tubule epithelial cells and transfected HEK 293T cells, through activation of IRS1, PI3/Akt, MEK/ERK, and p38 MAPK; urate uptake was inhibited in the presence of uricosuric drugs, specific inhibitors of protein tyrosine kinase, PI3 kinase (PI3K), ERK, and p38 MAPK. In X. laevis oocytes expressing ten individual urate transporters, IGF-1 through endogenous IGF-1R stimulated urate transport mediated by GLUT9, OAT1, OAT3, ABCG2, and ABCC4 and inhibited insulin's stimulatory action on GLUT9a and OAT3. IGF-1 significantly activated Akt and ERK. Specific inhibitors of PI3K, ERK, and PKC significantly affected IGF-1 stimulation of urate transport in oocytes. ConclusionsThe combined results of infusion, genetics, and transport experiments suggest that IGF-1 reduces SU by activating urate secretory transporters and inhibiting insulin's action.

Pathogenic Variants of SLC22A12 (URAT1) and SLC2A9 (GLUT9) in Spanish Patients with Renal Hypouricemia: Founder Effect of SLC2A9 Variant c.374C>T; p.(T125M)

“…The regulation of these transporters is complex and takes place at different levels such as transcription and post-translation, and various signaling pathways are involved [42,43]. Recent results suggest that GLUT9 is regulated by insulin/insulin receptor signaling through PI3K/Akt activation, and by insulin-like growth factor-1 and its receptor through the activation of insulin receptor substrate 1, PI3/Akt, MEK/ERK, and p38 MAPK [44,45]. On the other hand, two PDZ domain-containing proteins PDZK1 and NHERF1 seem to regulate the transport activity of URAT1 via interaction with its PDZ motif located in the intracellular C-terminal region [46,47].…”

GWAS-identified hyperuricemia-associated IGF1R variant rs6598541 has a limited role in urate mediated inflammation in human mononuclear cells

“…As reported by Kottgen et al, the urate-associated IGF1R rs6598541 variant is also associated to lower fractional excretion of urate, supporting a role of the IGF1-IGF1R axis on urate transport. This is supported by data showing that, in Xenopus laevis oocytes expressing human IGF1R and urate transporters, IGF-1 promotes urate uptake via IGF1R 39 . Therefore IGF1R association to gout is most probably exerted via urate control rather than inflammatory mechanisms, via IGF1R, GLUT9 expression and activation, leading to urate reabsorbtion 42 .…”

“…IGF1R genetic variants are potentially functionally relevant in gout and hyperuricemia since the genetic control of urate levels and risk of gout at the IGF1R locus also colocalizes with genetic control of IGF1R expression data 23 . For IGF1R rs6598541, the gout risk and elevated serum urate associated allele A is associated with lower IGF1R expression in heart tissue (left ventricle) 39 . In our study, when assessing freshly isolated PBMCs from patients with gout or controls we did not observe association of IGF1R gene expression with rs6598541.…”

Uric Acid Metabolic Disorders in Pituitary-Target Gland Axis

“… 86 With respect to IGF-1, a recent study proposed that it stimulates UA transport mediated by GLUT9, OAT1, OAT3, ABCG2, and ABCC4 via Akt and ERK pathways while inhibiting insulin’s effect on GLUT9a ( Figure 3 ). 87 …”