Related Experiment Video
Updated: Jun 23, 2026
Hyperinsulinemic-euglycemic Clamps in Conscious, Unrestrained Mice
Published on: November 16, 2011
Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration
Surabhi Bangarbale1, Blythe D Shepard2, Shivani Bansal3
1Department of Medicine, Georgetown University, Washington, DC 20057, USA.
Abstract:
Sodium glucose cotransporter, type 2 inhibitors, such as Empagliflozin, are protective of the kidneys by unclear mechanisms. Our aim was to determine how Empagliflozin affected kidney cortical metabolome and lipidome in mice. Adult male TALLYHO mice (prone to obesity) were treated with a high-milk-fat diet, or this diet containing Empagliflozin (0.01%), for 8 weeks. Targeted and untargeted metabolomics and lipidomics were conducted on kidney cortex by liquid chromatography followed by tandem mass-spectroscopy. Metabolites were statistically analyzed by MetaboAnalyst 5.0, LipidSig (lipid species only) and/or CEU Mass Mediator (untargeted annotation). In general, volcano plotting revealed oppositely skewed patterns for targeted metabolites (primarily hydrophilic) and lipids (hydrophobic) in that polar metabolites showed a larger number of decreased species, while non-polar (lipids) had a greater number of increased species (>20% changed and/or raw p-value < 0.05). The top three pathways regulated by Empagliflozin were urea cycle, spermine/spermidine biosynthesis, and aspartate metabolism, with an amino acid network being highly affected, with 14 of 20 classic amino acids down-regulated. Out of 75 changed polar metabolites, only three were up-regulated, i.e., flavin mononucleotide (FMN), uridine, and ureidosuccinic acid. Both FMN and uridine have been shown to be protective of the kidney. Scrutiny of metabolites of glycolysis/gluconeogenesis/Krebs cycle revealed a 20−45% reduction in several species, including phosphoenolpyruvate (PEP), succinate, and malic acid. In contrast, although overall lipid quantity was not higher, several lipid species were increased by EMPA, including those of the classes, phosphatidic acids, phosphatidylcholines, and carnitines. Overall, these analyses suggest a protection from extensive metabolic load and the corresponding oxidative stress with EMPA in kidney. This may be in response to reduced energy demands of the proximal tubule as a result of inhibition of transport and/or differences in metabolic pools available for metabolism.
Insights
Empagliflozin (a SGLT2 inhibitor) alters kidney metabolism, decreasing polar metabolites and increasing lipids. This suggests Empagliflozin protects kidneys by reducing metabolic load and oxidative stress.
Area of Science:
- Metabolomics and lipidomics research
- Renal physiology and pharmacology
- Biochemistry of kidney function
Background:
- Sodium glucose cotransporter type 2 (SGLT2) inhibitors, like Empagliflozin, offer kidney protection through mechanisms not fully understood.
- Obesity and high-fat diets can impose significant metabolic stress on the kidneys.
Purpose of the Study:
- To investigate the impact of Empagliflozin on the kidney cortical metabolome and lipidome in mice.
- To elucidate potential mechanisms behind Empagliflozin's renal protective effects.
Main Methods:
- Adult male TALLYHO mice were fed a high-milk-fat diet, with or without Empagliflozin, for 8 weeks.
- Kidney cortex samples underwent targeted and untargeted metabolomics and lipidomics using liquid chromatography-tandem mass spectrometry.
- Statistical analysis was performed using MetaboAnalyst 5.0, LipidSig, and CEU Mass Mediator.
Main Results:
- Empagliflozin treatment resulted in decreased polar metabolites and increased lipid species in the kidney cortex.
- Key affected pathways included the urea cycle, spermine/spermidine biosynthesis, and aspartate metabolism, with significant down-regulation of amino acids.
- Reduced levels of glycolysis and Krebs cycle intermediates were observed, alongside increases in specific lipid classes like phosphatidic acids and phosphatidylcholines.
Conclusions:
- Empagliflozin appears to protect the kidney by mitigating metabolic load and associated oxidative stress.
- This protection may stem from reduced proximal tubule energy demands due to transport inhibition and altered metabolic substrate availability.
Related Concept Videos
01:25Pharmacokinetics in Obese Patients: Drug Absorption and Distribution
01:20Pharmacokinetics in Obese Patients: Drug Metabolism and Excretion