Insulin stimulates uric acid reabsorption via regulating urate transporter 1 and ATP-binding cassette subfamily G member 2

Abstract

Accumulating data indicate that renal uric acid (UA) handling is altered in diabetes and by hypoglycemic agents. 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 hypoglycemic agents alter the levels of renal urate transporters. In insulin-depleted diabetic rats with streptozotocin treatment, both UA excretion and fractional excretion of UA 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 subfamily G member 2 (ABCG2) was increased, consistent with the increased renal UA clearance. Administration of insulin to the diabetic rats decreased UA excretion and alleviated UA transporter-level changes, while sodium glucose cotransporter 2 inhibitor (SGLT2i) ipragliflozin did not change renal UA handling in this model. To confirm the contribution of insulin in the regulation of urate transporters, normal rats received insulin and separately, ipragliflozin. Insulin significantly increased URAT1 and decreased ABCG2 levels, resulting in increased UA reabsorption. In contrast, the SGLT2i did not alter URAT1 or ABCG2 levels, although blood glucose levels were similarly reduced. Furthermore, we found that insulin significantly increased endogenous URAT1 levels in the membrane fraction of NRK-52E cells, the kidney epithelial cell line, demonstrating the direct effects of insulin on renal UA transport mechanisms. 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.

Short-Communication: Ingestion of a Nucleotide-Rich Mixed Meal Increases Serum Uric Acid Concentrations but Does Not Affect Postprandial Blood Glucose or Serum Insulin Responses in Young Adults

“…The mechanism by which nucleotide rich meal ingestion elevates circulating uric acid concentrations likely relates to increased uric acid production as a metabolic end-product without any appreciable increase in (at least over the immediate postprandial period) urinary clearance. While we did not collect urine samples to confirm this, recent animal data report that experimental alterations in circulating uric acid concentrations are regulated at the level of renal handling [18]. However, this work also suggested that the direct mechanism was the level of circulating insulin, which is not consistent with our finding of equivalent postprandial insulin responses across conditions.…”

Empagliflozin Attenuates Hyperuricemia by Upregulation of ABCG2 via AMPK/AKT/CREB Signaling Pathway in Type 2 Diabetic Mice

“…SGLT2 inhibitors have recently emerged as a promising novel class of glucose lowering drugs to facilitate glucose excretion in urine independent of insulin [35]. Accumulating data indicated their antihyperuricemic effects in both clinical [18,19,36] and basic studies [37,38]. One of basic studies performed in vitro using Xenopus oocytes indicated that luseogliflozin lowered the SUA level due to inhibition of UA reabsorption mediated by GLUT9 isoform 2 at the collecting duct of the renal tubule [38].…”

“…One of basic studies performed in vitro using Xenopus oocytes indicated that luseogliflozin lowered the SUA level due to inhibition of UA reabsorption mediated by GLUT9 isoform 2 at the collecting duct of the renal tubule [38]. Another study conducted in STZ-induced diabetic rats suggested that empagliflozin may exert anti-hyperuricemic effects via regulating URAT1 and ABCG2 [37]. However, our study demonstrated that empagliflozin promoted ABCG2 expression in kidney and ileum in KK-Ay mice with HUA, but has little impact on the other transporters.…”

Sodium-glucose co-transporter 2 inhibitors and serum uric acid

“…Namely, GLUT9 isoform 2 is expressed at the apical membrane of the kidney tubular cells and transports both uric acid (UA) and glucose. In addition, insulin increases urate transporter 1 and decreases ATP-binding cassette subfamily G member 2 levels, resulting in increased UA reabsorption 6,7 .…”