Kidney Proximal Tubule GLUT2-More than Meets the Eye

Tubulopathy plays a central role in the pathophysiology of diabetic kidney disease (DKD). Under diabetic conditions, the kidney proximal tubule cells (KPTCs) are exposed to an extensive amount of nutrients, most notably glucose; these nutrients deteriorate KPTCs function and promote the development and progression of DKD. Recently, the facilitative glucose transporter 2 (GLUT2) in KPTCs has emerged as a central regulator in the pathogenesis of DKD. This has been demonstrated by identifying its specific role in enhancing glucose reabsorption and glucotoxicity, and by deciphering its effect in regulating the expression of the sodium-glucose transporter 2 (SGLT2) in KPTCs. Moreover, reduction/deletion of KPTC-GLUT2 has been recently found to ameliorate DKD, raising the plausible idea of considering it as a therapeutic target against DKD. However, the underlying molecular mechanisms by which GLUT2 exerts its deleterious effects in KPTCs remain vague. Herein, we review the current findings on the proximal tubule GLUT2 biology and function under physiologic conditions, and its involvement in the pathophysiology of DKD. Furthermore, we shed new light on its cellular regulation during diabetic conditions.

Automated summary

Tubulopathy is crucial in the pathophysiology of diabetic kidney disease (DKD), particularly the role of GLUT2 in promoting glucose reabsorption and glucotoxicity, as well as regulating SGLT2 expression in kidney proximal tubule cells (KPTCs). Reduction/deletion of KPTC-GLUT2 has shown promising results in ameliorating DKD, making it a potential therapeutic target. However, the molecular mechanisms underlying the deleterious effects of GLUT2 in KPTCs remain unclear.