Sotagliflozin reduces glucose absorption and improves ultrafiltration in a rat model of chronic peritoneal exposure to high-glucose dialysate.

Introduction: Unwanted glucose exposure and absorption during peritoneal dialysis (PD) remain clinical challenges. Recent studies have attempted to reduce glucose absorption in PD via use of selective sodium glucose cotransporter 2 (SGLT2) inhibitors, but results have been inconsistent and even paradoxical. We aimed to (i) explore whether both SGLT1 and SGLT2 are expressed and their respective anatomical localizations and proportions in the peritoneum and (ii) elucidate whether dual SGLT1/SGLT2 inhibition could reduce glucose absorption and improve ultrafiltration using a uremia chronic PD rat model.

Methods: 24 male Sprague‒Dawley rats were randomly divided into four groups (each n=6): the sham operation group, uremia group, uremia PD group and sotagliflozin-treated group (a dual SGLT1+2 inhibitor). The expression levels of both SGLT1 and SGLT2 were determined by immunohistochemistry and western blot analysis. Peritoneal transport function was monitored via a peritoneal equilibration test (PET).

Results: Both SGLT1 and SGLT2 are comparably expressed in the rat peritoneum and are prominently located in the vascular endothelium and peritoneal mesothelium. Compared with sham controls, uremia rats presented significantly increased expressions of both SGLT1 and SGLT2, and their expressions were further significantly increased after high glucose PDF exposure for 5 weeks but markedly reversed by sotagliflozin cotreatment. Compared with the sham controls, uremia rats were characterized by greater glucose absorption, increased blood glucose levels, a lower D/D0 glucose ratio, a higher D/P cr ratio, a higher D/P urea ratio, and less net ultrafiltration. After infusion of high glucose PDF for 5 weeks, these changes were more marked and were substantially ameliorated by sotagliflozin cotreatment.

Conclusions: High glucose PDF significantly increased the peritoneal expressions of both SGLT1 and SGLT2, which in turn facilitated more glucose absorption, eventually leading to a vicious cycle. Sotagliflozin may emerge as a novel strategy in PD to reduce glucose diffusion and enhance ultrafiltration.