Phloretin Improves Ultrafiltration and Reduces Glucose Absorption during Peritoneal Dialysis in Rats

Abstract

Background: Harmful glucose exposure and absorption remain major limitations of peritoneal dialysis (PD). We previously showed that inhibition of sodium glucose cotransporter 2 did not affect glucose transport during PD in rats. However, more recently, we found that phlorizin, a dual blocker of sodium glucose cotransporters 1 and 2, reduces glucose diffusion in PD. Therefore, either inhibiting sodium glucose cotransporter 1 or blocking facilitative glucose channels by phlorizin metabolite phloretin would reduce glucose transport in PD.

Methods: We tested a selective blocker of sodium glucose cotransporter 1, mizagliflozin, as well as phloretin, a nonselective blocker of facilitative glucose channels, in an anesthetized Sprague-Dawley rat model of PD.

Results: Intraperitoneal phloretin treatment reduced glucose absorption by >30% and resulted in a >50% higher ultrafiltration rate compared with control animals. Sodium removal and sodium clearances were similarly improved, whereas the amount of ultrafiltration per millimole of sodium removed did not differ. Mizagliflozin did not influence glucose transport or osmotic water transport.

Conclusions: Taken together, our results and previous results indicate that blockers of facilitative glucose channels may be a promising target for reducing glucose absorption and improving ultrafiltration efficiency in PD.

Keywords: glucose; peritoneal dialysis; peritoneal membrane; phloretin; ultrafiltration; water transport.

Graphical abstract

Figure 1.

Summary of peritoneal glucose transporter targets and tested drugs. Solid symbols indicate inhibitory effects.

Figure 2.

Schematic of the experimental setup. PD with 1.5% glucose fluid with or without intraperitoneal phloretin or mizagliflozin was performed in anesthetized Sprague–Dawley rats using a fill volume of 20 ml.

Figure 3.

Forest plot of phloretin treatment effects. 95% CIs of the phloretin effect after 30 and 60 minutes on glucose and urea diffusion capacity (MTAC), UF rate, and sodium removal compared with the sham group. Interval markers represent the medians of the difference.

Figure 4.

Phloretin effect on volume and small solute transport. (A) Intraperitoneal volume as a function of dwell time estimated in phloretin-treated animals compared with sham. The solid line represents nonlinear regression in drug-exposed animals, whereas the dashed line represents the control group. (B and C) D/D₀ ratios of glucose and creatinine at 1, 30, and 60 minutes. (D) Urea dialysate to plasma ratios at 30 and 60 minutes in phloretin-exposed animals and controls. The solid line represents nonlinear regression in drug-exposed animals, whereas the dashed line represents the control group. **, P<0.01. NS, not significant.