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Abstract: TH-PO351

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

Session Information

Category: Fluid‚ Electrolyte‚ and Acid-Base Disorders

  • 1001 Fluid‚ Electrolyte‚ and Acid-Base Disorders: Basic


  • Mount, David B., Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Leask, Megan P., Division of Rheumatology and Clinical Immunology, University of Alabama, Birmingham, Alabama, United States
  • Merriman, Tony, Division of Rheumatology and Clinical Immunology, University of Alabama, Birmingham, Alabama, United States
  • Mandal, Asim, Brigham and Women's Hospital, Boston, Massachusetts, United States

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 impacts on SU levels.


Co-localization analyses of SU GWAS signal at IGF1R and eQTL signals in cis using COLOC2; RT-PCR, Western blotting, and urate transport assays in a proximal tubule cell line, transfected HEK 293T cells, and Xenopus laevis oocytes.


Genetic association at IGF1R with SU is stronger in women and is mediated by control of IGF1R expression. Epistatic interaction between IGF1R and each of SLC2A9 and ABCG2 was found to affect SU differentially between men and women. IGF-1, via IGF-1R, stimulated urate uptake in human renal proximal tubule epithelial cells (PTC-05) and transfected HEK 293T cells, through activation of IRS1, PI3K/Akt, MEK/ERK and p38 MAPK; urate uptake was inhibited in the presence of uricosuric drugs, specific inhibitors of protein tyrosine kinase (PTK), PI3 kinase (PI3K), ERK and p38 MAPK. In Xenopus laevis oocytes expressing individual urate transporters, IGF-1 via 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 and IGF-1-stimulation of urate transport was significantly affected by specific inhibitors of PI3K, ERK and PKC in oocytes.


The combined results of infusion, genetics, and transport experiments suggest that IGF-1 reduces SU by activating urate secretory transporters and inhibiting insulin’s action. IGF-1 antagonizes the effects of insulin on urate transporters, indicating complex interactions in hyperuricemia associated with metabolic syndrome and hyperinsulinemia.


  • Other NIH Support