Empagliflozin ameliorates symptoms of diabetes and renal tubular dysfunction in a rat model of diabetes with enlarged kidney (DEK)

Abstract

Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used to reduce hyperglycemia. The present study investigated the effects of a SGLT2 inhibitor, empagliflozin, on hyperglycemia in a novel rat model of non-obesity type 2 diabetes with enlarged kidney (DEK). Methods Male DEK rats with non-fasting blood glucose concentrations ≤300 mg/dl and >300 mg/dl were classified as nondiabetic and diabetic, respectively. Groups of nondiabetic (control) and diabetic (DM-cont) rats were fed standard chow for 12 weeks, whereas another group of diabetic (DM-empa) rats was fed standard chow containing empagliflozin (300 mg/kg/day) for 12 weeks. Blood glucose, body weight, glucose tolerance, food and water intake, urinary volume, plasma and urinary biochemical parameters, and bone mineral density were measured, and their kidneys and pancreas histologically analyzed. Results Treatment with empagliflozin reduced blood glucose concentration and food intake in diabetic rats, but inhibited loss of adeps renis and led to body weight gain. Empagliflozin attenuated polyuria and polydipsia but increased plasma concentrations of total cholesterol, sodium and total protein toward normal level. Empagliflozin also significantly reduced urinary excretion of proteins and electrolytes and restored bone mineral density and plasma concentrations of valine and isoleucine to normal levels. Moreover, dilation of renal tubules and kidney enlargement were not attenuated in the DM-empa group. Conclusion The response of DEK rats to empagliflozin differed from that of other diabetic animal models, suggesting that DEK rats have unique characters for studying and evaluating the multiple biological effects of SGLT2 inhibitors. These findings also indicted that empagliflozin could ameliorate systemic metabolism and improve renal tubule function in diabetic condition.

Characterization of Enlarged Kidneys and Their Potential for Inducing Diabetes in DEK Rats

“…We found that body weight gain was inhibited in Sham operated rats, as shown in non-treated DEK-DM rats [17,22]. In contrast, body weight gradually increased with age in 1/2Nx rats, with body weight after 21 days being significantly higher in 1/2Nx than in Sham operated rats (Figure 4a).…”

“…Since blood glucose concentrations in these 1/2Nx rats were almost normal, hyperglycemia was not considered a major cause of renal enlargement. Similarly, our previous study revealed that the normalization of blood glucose level by the administration of empagliflozin did not prevent renal enlargement in DEK-DM rats [22]. Therefore, the intrinsic growth ability of these kidneys may be enhanced by 1/2Nx.…”

“…To evaluate metabolic status and renal function, biochemical parameters were measured in plasma and urine. A previous comparison of DEK-DM and DEK-cont rats showed that plasma Cre, Tcho, electrolytes, Alb, and TP concentrations were lower, while excretion of Glu, urea nitrogen, electrolytes, and protein into urine were higher, in DEK-DM than in DEK-cont rats [17,22]. This condition was partially reversed by 1/2Nx (Tables 3 and 4).…”

“…1/2Nx was also found to increase the plasma concentrations of Tcho, Na, Alb, and TP and to reduce the urinary excretions of glucose, UN, and protein in DEK-DM rats. Interestingly, these alterations were also observed in DEK-DM rats treated with empagliflozin [22], suggesting that these alterations may have been due to improvements in negative energy balance resulting from easing of diabetic conditions. That is, the conversion from a hypercatabolic to an anabolic state may reduce the production of urea nitrogen and enhance the production in the liver of plasma proteins, including albumin.…”

“…In addition, SGLT2 inhibitors may inhibit renal glycogenesis under prediabetic conditions [29]. Long-term administration of the SGLT2 inhibitor, empagliflozin, reduced blood glucose level and improved systemic conditions in DEK-DM rats [22]. In addition, 1/2Nx was found to increase insulin sensitivity, whereas uremic conditions reduce this sensitivity, in Wistar rats, suggesting that reduced gluconeogenesis capacity resulted from the partial improvement in insulin resistance induced by 1/2Nx [33].…”