Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats

Chen, Ling; LaRocque, Lauren LaRocque; Efe, Orhan; Wang, Juan; Sands, Jeff M.; Klein, Janet D.

doi:10.1016/j.amjms.2016.08.015

Cited by 41 publications

(39 citation statements)

References 30 publications

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“…Excessive urination is a symptom of diabetes and is due to the inability of the renal tubules to absorb glucose filtered in the glomeruli leading to osmotic diuresis [36]. Similarly, in our study urine volume was significantly increased in diabetic rats compared to control rats.…”

Section: Discussionsupporting

confidence: 77%

Anti-Hyperglycemic Effect of Terminalia Catappa Fruit Extract in Streptozotocin-Induced Diabetic Rats

Behl¹,

Kotwani²

2017

Int J Pharm Pharm Sci

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Objective: To explore the anti-hyperglycemic effect of fruit extract of Terminalia catappa (Indian almond), a potential medicine from plant origin in a diabetic rat model.Methods: Streptozotocin-induced chronic diabetic rat model was utilized in the study. Three doses of test drug, hydro-alcoholic fruit extract of Terminalia catappa in 20 mg/kg, 30 mg/kg and 40 mg/kg and a standard anti-diabetic drug, glibenclamide (10 mg/kg) was used. The study had a total of nine groups with eight animals in each group. Drugs were given orally every day for 12 w. Blood glucose, body weight and urine volume were measured weekly, glycosylated hemoglobin (HbA1c) was estimated at 12th week in all groups. Data for all parameters were analyzed using one-way ANOVA repeated measures followed by Mann-Whitney test.Results: Hydro-alcoholic fruit extract of T. catappa significantly decreased blood glucose, urine volume and increased body weight in a dose-dependent manner in diabetic rats. At 12th week, blood glucose level in control, diabetic control, glibenclamide, T. catappa (40 mg/kg) group was 96.25±2.05 mg/dl, 599.75±0.25 mg/dl, 248.25±11.45 mg/dl, 115.00±3.78 mg/dl respectively. Effect of T. catappa in 30 mg/kg and 40 mg/kg dose was significantly more than glibenclamide. At 12th week, HbA1c level in control, diabetic control, glibenclamide, T. catappa (40 mg/kg) was 2.94±0.33 mmol/l, 4.94±0.49 mmol/l, 3.61±0.28 mmol/l, 3.21±0.27 mmol/l. Treatment with T. catappa 30 mg/kg, 40 mg/kg and glibenclamide brought back the level of HbA1c to normal levels. The addition of glibenclamide to T. catappa (40 mg/kg) did not produce any additional effect on blood glucose and HbA1c levels compared to the effect of T. catappa (40 mg/kg) in diabetic rats.Conclusion: Terminalia catappa fruit extract exhibited a significant anti-hyperglycemic effect in diabetic rats and has a great potential to be used in diabetes.

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Section: Discussionsupporting

confidence: 77%

Anti-Hyperglycemic Effect of Terminalia Catappa Fruit Extract in Streptozotocin-Induced Diabetic Rats

Behl¹,

Kotwani²

2017

Int J Pharm Pharm Sci

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“…Diabetic patients frequently present with electrolyte abnormalities [12]. The diuretic effects of SGLT2i may influence the serum chloride concentration, but few experimental [13][14][15] and clinical studies [16,17] have deeply evaluated the effects and mechanistic consideration of SGLT2i on the serum chloride levels. The findings of the present study indicate that SGLT2i preserves or enhances the serum chloride concentration in T2DM/ non-HF patients.…”

Section: Discussionmentioning

confidence: 99%

Enhancement of the serum chloride concentration by administration of sodium–glucose cotransporter-2 inhibitor and its mechanisms and clinical significance in type 2 diabetic patients: a pilot study

Kataoka

Yoshida

2020

Diabetol Metab Syndr

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Background: Chloride is a key electrolyte that regulates the body fluid distribution. Accordingly, manipulating chloride kinetics by selecting a suitable diuretic could be an attractive strategy for correcting body fluid dysregulation. Therefore, this study examined the effects and contributing factors of a sodium-glucose cotransporter-2 inhibitor (SGLT2i) on the serum chloride concentration in type 2 diabetic (T2DM) patients without heart failure (HF). Methods: This study was a retrospective single-center observational study that enrolled 10 T2DM/non-HF outpatients for whom the SGLT2i empagliflozin (daily oral dose of 10 mg) was prescribed. Among these 10 patients, 6 underwent detailed clinical testing that included hormonal and metabolic blood tests. Results: Empagliflozin treatment for 1-2 months decreased body weight (− 2.69 ± 1.9 kg; p = 0.002) and HbA1c (− 0.88 ± 0.55%; p = 0.0007). The hemoglobin (+ 0.27 ± 0.36 g/dL; p = 0.04) and hematocrit (+ 1.34 ± 1.38%; p = 0.014) values increased, but the serum creatinine concentration remained unchanged. The serum chloride concentration increased from 104 ± 3.23 to 106 ± 2.80 mEq/L (p = 0.004), but the sodium and potassium concentrations did not change. The spot urinary sodium concentration decreased from 159 ± 43 to 98 ± 35 mEq/L (p < 0.02) and the spot urinary chloride tended to decrease (from 162 ± 59 to 104 ± 36 mEq/L, p < 0.08). Both renin and aldosterone tended to be activated (5/6, 83%). The strong organic acid metabolite concentrations of serum acetoacetate (from 42 ± 25 to 100 ± 45 μmol/L, p < 0.02) and total ketone bodies (from 112 ± 64 to 300 ± 177 μmol/L, p < 0.04) increased, but the actual HCO 3 − concentration decreased (from 27 ± 2.5 to 24 ± 1.6 mEq/L, p < 0.008). Conclusions: The present study demonstrated that SGLT2i enhances the serum chloride concentration in T2DM patients and suggests that the effect is mediated by the possible following mechanisms: (1) enhanced reabsorption of urinary chloride by aldosterone activation due to blood pressure lowering and blood vessel contraction effects, (2) reciprocal increase in the serum chloride concentration by reducing the serum HCO 3 − concentration via a buffering effect of strong organic acid metabolites, and (3) reduced NaHCO 3 reabsorption and concurrently enhanced chloride reabsorption in the urinary tubules by inhibiting Na +-H + exchanger 3 in the renal proximal tubules. Thus, the diuretic

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“…Inhibition of Na + reabsorption in the PT will switch on compensatory systems in more distally located segments to counteract the proximal Na + loss. A recent study has shown that dapagliflozin treatment upregulated the expression of urea transporter-A1, aquaporin-2, and NKCC2 proteins [1]. However, little is known about the effects of SGLT2 inhibitors on the local and downstream Na + transporters.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study has found that treatment with an SGLT2 inhibitor increases the expression of urea transporter-A1, aquaporin-2 and NKCC2 proteins [1]. However, a systematic analysis of the compensatory mechanisms that regulate renal Na + reabsorption after SGLT2 treatment is lacking.…”

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Effect of Dapagliflozin Treatment on the Expression of Renal Sodium Transporters/Channels on High-Fat Diet Diabetic Mice

Baaij

Millar

Gault

et al. 2019

Nephron

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Background: Inhibition of the Na⁺/glucose co-transporter 2 is a new therapeutic strategy for diabetes. It is unclear how proximal loss of Na⁺ (and glucose) affects the subsequent Na⁺ transporters in the proximal tubule (PT), thick ascending limb of loop of Henle (TAL), distal convoluted tubule (DCT) and collecting duct (CD). Methods: Mice on a high fat diet were administered 3 doses streptozotocin 6 days prior to oral dapagliflozin administration or vehicle for 18 days. A control group of lean mice were also included. Body weight and glucose were recorded at regular intervals during treatment. Renal Na⁺ transporters expression in nephron segments were analyzed by RT-qPCR and Western blot. Results: Dapagliflozin treatment resulted in a significant reduction in body weight and blood glucose compared to vehicle-treated controls. mRNA results showed that Na⁺-hydrogen antiporter 3 (NHE3), Na⁺/phosphate cotransporter (NaPi-2a) and epithelial Na⁺ channel expression was increased, Ncx1, ENaCβ and ENaCγ expression declined (p all < 0.05), respectively, in dapagliflozin-treated mice when compared with saline vehicle mice. Na-K-2Cl cotransporters and Na-Cl cotransporter mRNA expression was not affected by dapagliflozin treatment. Na⁺/K⁺-ATPase (Atp1b1) expression was also increased significantly by dapagliflozin treatment, but it did not affect Atp1a1 and glucose transporter 2 expression. Western blot analysis showed that NaPi-2a, NHE3 and ATP1b1 expression was upregulated in dapagliflozin-treated diabetic mice when compared with saline vehicle mice (p < 0.05). Conclusion: Our findings suggest that dapagliflozin treatment augments compensatory changes in the renal PT in diabetic mice.

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Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats

Cited by 41 publications

References 30 publications

Anti-Hyperglycemic Effect of Terminalia Catappa Fruit Extract in Streptozotocin-Induced Diabetic Rats

Anti-Hyperglycemic Effect of Terminalia Catappa Fruit Extract in Streptozotocin-Induced Diabetic Rats

Enhancement of the serum chloride concentration by administration of sodium–glucose cotransporter-2 inhibitor and its mechanisms and clinical significance in type 2 diabetic patients: a pilot study

Effect of Dapagliflozin Treatment on the Expression of Renal Sodium Transporters/Channels on High-Fat Diet Diabetic Mice

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