Sodium glucose cotransporter-2 (SGLT-2) is responsible for glucose reabsorption via the kidney. Empagliflozin is a selective SGLT-2 inhibitor that blocks the uptake of [14C]-AMG via human SGLT-2 (hSGLT-2) with an IC50 value of 3.1nM in vitro. It exhibited >2500-, >3500-, >350-, and >600-fold selectivity over hSGLT-1 (IC50 = 8.3μM), hSGLT-4 (IC50 = 11μM), hSGLT-5 (IC50 = 1.1μM), and hSGLT-6 (IC50 = 2.0μM), respectively. In kinetic binding experiments, [3H]-empagliflozin showed a high affinity for SGLT-2 (Kd = 57nM) in the absence of glucose, whereas glucose at 20nM lowered the affinity of empagliflozin to a Kd value of 194nM[8]. In db/db mice, treatment with empagliflozin (10mg/kg/day in food) for 4 weeks decreased the ventricular mass, lowered the fasting glucose level and elevated the fed and fasted ketone levels as compared to the vehicle-treated group. In the presence of insulin, empagliflozin-treated db/db mice showed increased mean palmitate oxidation rate in the heart in comparison to C57BL/6J mice. The cardiac ATP production rate in vehicle-treated db/db mice was 36% lower than that in C57BL/6J mice, whereas empagliflozin treatment restored the ATP production rate to the level similar to that in C57BL/6J mice[9].
作用机制
Empagliflozin is a potent and selective inhibitor of SGLT-2. It binds to SGLT-2 in a glucose-competitive manner[8].
Empagliflozin/恩格列净 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HL-1 cardiomyocytes
10 µM
48 h
Empagliflozin significantly downregulated the expression of CHOP and PARP-CL in LMNA R321X cardiomyocytes and reduced PERK phosphorylation, restoring AKT phosphorylation levels, indicating its ability to alleviate ER stress by inhibiting PERK activation.
J Transl Med. 2023 May 22;21(1):340.
AS podocytes
500 nM
48 h
Empagliflozin reduces lipid droplet accumulation and apoptosis in AS podocytes.
Elife. 2023 May 2;12:e83353.
AS podocytes
500 nM
48 h
Empagliflozin inhibits the utilization of glucose/pyruvate as a metabolic substrate in AS podocytes.
Elife. 2023 May 2;12:e83353.
HL7702 cells
10 μM
48 h
Empagliflozin significantly attenuated lipid accumulation in the PA and HG-induced hepatocyte steatosis model and upregulated autophagy and the AMPK-TET2 signaling pathway.
Front Pharmacol. 2021 Jan 20;11:622153.
Zebrafish ventricular cardiomyocytes
5 μM
2 h
To investigate the effects of Empagliflozin on major ionic currents, results showed that Empagliflozin increased the rapid and slow components of delayed rectifier potassium current (IKr and IKs), but had no effect on sodium current (INa), L-type and T-type calcium currents (ICaL and ICaT).
Int J Mol Sci. 2022 Aug 23;23(17):9559.
HepG2 hepatocytes
500 nM
24 h or 72 h
Empagliflozin protected hepatocytes under hyperglycemic conditions, reduced intracellular lipid accumulation and cellular senescence
Int J Mol Sci. 2021 Sep 30;22(19):10606.
3T3-L1 adipocytes
500 nM
Empagliflozin increased intracellular lipid accumulation in adipocytes under hyperglycemic conditions and reduced cellular senescence
Int J Mol Sci. 2021 Sep 30;22(19):10606.
Empagliflozin/恩格列净 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 N mice
Choline-deficient high-fat diet (CD-HFD)-induced NASH model
Oral gavage
10 mg/kg
Once daily for 12 weeks
Empagliflozin significantly reduced total in CD-HFD-fed mice and improved insulin resistance and glucose tolerance.
Exp Mol Med. 2023 Nov;55(11):2332-2345
Mice
CRS-3 model
Oral gavage
10 mg/kg
Once daily for 7 days
Empagliflozin improved cardiac function, alleviated myocardial inflammation and oxidative stress, and maintained mitochondrial structure and function.
Mol Metab. 2022 Oct;64:101553
Mice
Diabetes model
Oral
10 mg/kg
Once daily for 4 weeks
To evaluate the effect of Empagliflozin on cardiac energy production in diabetic mice. Results showed that Empagliflozin treatment significantly increased cardiac ATP production and prevented heart failure.
JACC Basic Transl Sci. 2018 Aug 26;3(5):575-587
Mice
Myocardial Ischemia/Reperfusion (I/R) Injury Model
Oral
10 mg/kg
Once daily for 7 days
Empagliflozin attenuated cardiac microvascular I/R injury by activating the AMPK α1/ULK1/FUNDC1/mitophagy pathway, maintaining microvascular structure and function, and reducing inflammation and endothelial cell damage.
Redox Biol. 2022 Jun;52:102288
Mice
Alport syndrome model
Oral
70 mg/kg
Daily for 6 weeks
Empagliflozin prolongs the survival of AS mice, reduces albuminuria, and improves renal function.
Elife. 2023 May 2;12:e83353.
Db/db mice
Type 2 diabetes and metabolic associated fatty liver disease (MAFLD) model
Intragastrically
3.8 mg/kg
Once daily for eight weeks
Empagliflozin significantly reduced blood glucose and hepatic lipid accumulation in db/db mice and improved hepatic steatosis by activating the AMPK-TET2-autophagy pathway.
Front Pharmacol. 2021 Jan 20;11:622153.
Hereditary hypertriglyceridemic rats
Non-obese model of insulin resistance
Oral
10 mg/kg
Once daily for 6 weeks
Empagliflozin attenuated gain, improved insulin sensitivity, and reduced oxidative stress and inflammation in the liver and kidney
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