Complex Positive Effects of SGLT-2 Inhibitor Empagliflozin in the Liver, Kidney and Adipose Tissue of Hereditary Hypertriglyceridemic Rats: Possible Contribution of Attenuation of Cell Senescence and Oxidative Stress.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Adipose Tissue/*metabolism ; Benzhydryl Compounds/*administration & dosage ; Cellular Senescence/*drug effects ; Gluconeogenesis/*drug effects ; Glucosides/*administration & dosage ; Hypertriglyceridemia/*drug therapy ; Hypertriglyceridemia/*metabolism ; Hypoglycemic Agents/*administration & dosage ; Kidney/*metabolism ; Lipogenesis/*drug effects ; Liver/*metabolism ; Oxidative Stress/*drug effects ; Sodium-Glucose Transporter 2 Inhibitors/*administration & dosage; 3T3-L1 Cells ; Administration, Oral ; Animals ; Cell Survival/drug effects ; Disease Models, Animal ; Down-Regulation/drug effects ; Dyslipidemias/drug therapy ; Gluconeogenesis/genetics ; Hep G2 Cells ; Humans ; Insulin Resistance ; Lipogenesis/genetics ; Male ; Mice ; Rats ; Treatment Outcome ; Up-Regulation/drug effects ; Weight Gain/drug effects

(1) Background: empagliflozin, sodium-glucose co-transporter 2 (SGLT-2) inhibitor, is an effective antidiabetic agent with strong cardio- and nephroprotective properties. The mechanisms behind its cardio- and nephroprotection are still not fully clarified. (2) Methods: we used male hereditary hypertriglyceridemic (hHTG) rats, a non-obese model of dyslipidaemia, insulin resistance, and endothelial dysfunction fed standard diet with or without empagliflozin for six weeks to explore the molecular mechanisms of empagliflozin effects. Nuclear magnetic resonance (NMR)-based metabolomics; quantitative PCR of relevant genes involved in lipid and glucose metabolism, or senescence; glucose and palmitic acid oxidation in isolated tissues and cell lines of adipocytes and hepatocytes were used. (3) Results: empagliflozin inhibited weight gain and decreased adipose tissue weight, fasting blood glucose, and triglycerides and increased HDL-cholesterol. It also improved insulin sensitivity in white fat. NMR spectroscopy identified higher plasma concentrations of ketone bodies, ketogenic amino acid leucine and decreased levels of pyruvate and alanine. In the liver, adipose tissue and kidney, empagliflozin up-regulated expression of genes involved in gluconeogenesis and down-regulated expression of genes involved in lipogenesis along with reduction of markers of inflammation, oxidative stress and cell senescence. (4) Conclusion: multiple positive effects of empagliflozin, including reduced cell senescence and oxidative stress, could contribute to its long-term cardio- and nephroprotective actions.

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GA19-06199S Czech Science Foundation; IN 00023001 CZ - DRO ("Institute for Clinical and Experimental Medicine - IKEM")

Keywords: cell senescence; empagliflozin; hereditary hypertriglyceridemic rat model; hypertriglyceridemia; insulin sensitivity; metabolic syndrome

0 (Benzhydryl Compounds)
0 (Glucosides)
0 (Hypoglycemic Agents)
0 (Sodium-Glucose Transporter 2 Inhibitors)
HDC1R2M35U (empagliflozin)

Date Created: 20211013 Date Completed: 20211108 Latest Revision: 20211108

20231215

PMC8508693

10.3390/ijms221910606

34638943