Unmasking a sustained negative effect of SGLT2 inhibition on body fluid volume in the rat

Author:

Masuda Takahiro1ORCID,Watanabe Yuko1,Fukuda Keiko1,Watanabe Minami1,Onishi Akira1,Ohara Ken1,Imai Toshimi1,Koepsell Hermann2,Muto Shigeaki1,Vallon Volker3,Nagata Daisuke1

Affiliation:

1. Division of Nephrology, Department of Internal Medicine, Jichi Medical University, Shimotsuke, Japan

2. Department of Molecular Plant Physiology and Biophysics, Julius-von-Sachs-Institute, University of Würzburg, Würzburg, Germany

3. Division of Nephrology and Hypertension, Departments of Medicine and Pharmacology, University of California San Diego and VA San Diego Healthcare System, San Diego, CA

Abstract

The chronic intrinsic diuretic and natriuretic tone of sodium-glucose cotransporter 2 (SGLT2) inhibitors is incompletely understood because their effect on body fluid volume (BFV) has not been fully evaluated and because they often increase food and fluid intake at the same time. Here we first compared the effect of the SGLT2 inhibitor ipragliflozin (Ipra, 0.01% in diet for 8 wk) and vehicle (Veh) in Spontaneously Diabetic Torii rat, a nonobese type 2 diabetic model, and nondiabetic Sprague-Dawley rats. In nondiabetic rats, Ipra increased urinary excretion of Na+ (UNaV) and fluid (UV) associated with increased food and fluid intake. Diabetes increased these four parameters, but Ipra had no further effect, probably because of its antihyperglycemic effect, such that glucosuria and, as a consequence, food and fluid intake were unchanged. Fluid balance and BFV, determined by bioimpedance spectroscopy, were similar among the four groups. To study the impact of food and fluid intake, nondiabetic rats were treated for 7 days with Veh, Ipra, or Ipra+pair feeding+pair drinking (Pair-Ipra). Pair-Ipra maintained a small increase in UV and UNaV versus Veh despite similar food and fluid intake. Pair-Ipra induced a negative fluid balance and decreased BFV, whereas Ipra or Veh had no significant effect compared with basal values. In conclusion, SGLT2 inhibition induces a sustained diuretic and natriuretic tone. Homeostatic mechanisms are activated to stabilize BFV, including compensatory increases in fluid and food intake.

Funder

Grant-in-Aid for Young Scientists

Jichi Medical University Young Investigator Award

NIH grants

UAB/UCSD O'Brien Center of Acute Kidney Injury

Grant-in-Aid for Reserch on Advanced Chronic Kidney Disease, Practical Research Project for Renal Diseases from the Japan Agency for Medical Research and Development

Publisher

American Physiological Society

Subject

Physiology

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