Insulin stimulates SGLT2-mediated tubular glucose absorption via oxidative stress generation

Abstract

Background: Ninety percent of glucose filtered by the glomerulus is reabsorbed by a sodium-glucose cotransporter 2 (SGLT2), which is expressed mainly on the apical membrane of renal proximal tubules. Since SGLT-2-mediated glucose reabsorption is enhanced under diabetic conditions, selective inhibition of SGLT2 has been proposed as a potential therapeutic target for the treatment of patients with diabetes. However, it remains unclear which diabetes-associated factors are involved in overexpression of SGLT2. Methods: Therefore, in this study, we examined whether insulin, high glucose, advanced glycation end products (AGEs), or H 2 O 2 stimulated SGLT2 expression in human cultured proximal tubular cells, and then investigated the underlying molecular mechanisms. Results: High glucose or AGEs did not affect SGLT2 expression in tubular cells. Insulin significantly increased tubular SGLT2 level in a dose-dependent manner, whereas bell-shaped dose-response curves were observed for H 2 O 2 -treated cells. An anti-oxidant, N-acetylcysteine completely blocked insulin-induced up-regulation of SGLT2 as well as increase in glucose absorption by tubular cells. Furthermore, insulin dose-dependently increased reactive oxygen species generation in tubular cells. Conclusions: Our present study demonstrated that insulin could stimulate SGLT-2-mediated glucose entry into cultured proximal tubular cells via oxidative stress generation. Suppression of the insulin-induced overexpression of SGLT2 in tubular cells might be a novel therapeutic strategy for the treatment of diabetic nephropathy.