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Abstract: FR-PO628

Insulin Stimulates Urate Transporter 1 (URAT1) and Uric Acid Reabsorption

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Shibata, Shigeru, Teikyo University School of Medicine, Tokyo, Japan
  • Toyoki, Daigo, Teikyo University School of Medicine, Tokyo, Japan
  • Kuribayashi-Okuma, Emiko, Teikyo University School of Medicine, Tokyo, Japan
  • Nemoto, Yoshikazu, Teikyo University School of Medicine, Tokyo, Japan
  • Morimoto, Chikayuki, Teikyo University School of Medicine, Tokyo, Japan
  • Tamura, Yoshifuru, Teikyo University School of Medicine, Tokyo, Japan
  • Hosoyamada, Makoto, Teikyo University Faculty of Pharma-Sciences, Tokyo, Japan
  • Uchida, Shunya, Teikyo University School of Medicine, Tokyo, Japan
Background

Accumulating data indicate that renal uric acid (UA) handling is altered in diabetes. In addition, hyperinsulinemia is associated with hyperuricemia and hypouricosuria. However, the underlying mechanisms remain unclear. In this study, we aimed to investigate how diabetes and insulin alter the levels of renal UA transporters.

Methods

Sprague-Dawley (SD) rats received intraperitoneal injection of streptozotocin. The rats were confirmed to be diabetic by measuring blood glucose after 72 hours (glucose levels > 250 mg/dl). Some rats received subcutaneous infusion of insulin via an osmotic minipump (3 U/day). In a separate experiment, non-diabetic SD rats received a low dose of insulin (0.75 U/day). We also performed in vitro experiments using NRK-52E cells, the rat kidney epithelial cell line.

Results

In insulin-depleted diabetic rats with streptozotocin treatment, both UA excretion and fractional excretion of UA (FEUA) were increased, suggesting that tubular handling of UA is altered in this model. In the membrane fraction of the kidney, the expression of urate transporter 1 (URAT1) was significantly decreased, whereas that of ATP-binding cassette sub-family G member 2 (ABCG2) was increased, consistent with the increased renal UA clearance. Importantly, administration of insulin (3 U/day) to the diabetic rats decreased UA excretion and alleviated UA transporter level changes. To confirm the contribution of insulin in the regulation of urate transporters, normal rats received a low dose of insulin (0.75 U/day). Of note, insulin significantly increased URAT1 and decreased ABCG2 levels, resulting in increased UA reabsorption. Furthermore, URAT1 was present in NRK-52E cells, and the addition of insulin to the medium significantly increased the endogenous URAT1 levels in the membrane fraction of NRK-52E cells.

Conclusion

These results suggest a previously unrecognized mechanism for the anti-uricosuric effects of insulin, and provide novel insights into the renal UA handling in the diabetic state.