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.

Jaroslava Trnovska,Olena Oliyarnyk,Petr Svoboda,Hana Malinska,Martina Huttl,Milos Mraz,Katerina Rosolova,Vojtech Skop,Iveta Dvorakova,Helena Kratochvilova,Helena Pelantova,Martin Haluzik,Magdalena Melcova,Barbora Judita Kasperova,Sona Stemberkova-Hubackova,Irena Markova,Marek Kuzma

doi:10.3390/ijms221910606

Abstract

(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.

Highlights

The sedentary lifestyle accompanied by excessive energy intake leads to metabolic imbalance and increased risk of type 2 diabetes mellitus (T2DM), dyslipidaemia, arterial hypertension, non-alcoholic fatty liver disease (NAFDL) and other pathologies commonly referred to as metabolic or insulin resistance syndrome [1]
Empagliflozin treatment for six weeks attenuated body weight gain (Figure 1A) despite food intake, but not water intake was greater in empagliflozin treated rats (Figure 1B)
Increased glycosuria was detected after empagliflozin administration, while almost no glucose was detected in the urine of the control group (Table 1)

Summary

Introduction

The sedentary lifestyle accompanied by excessive energy intake leads to metabolic imbalance and increased risk of type 2 diabetes mellitus (T2DM), dyslipidaemia, arterial hypertension, non-alcoholic fatty liver disease (NAFDL) and other pathologies commonly referred to as metabolic or insulin resistance syndrome [1]. Obese patients with T2DM typically suffer from subclinical inflammation that is involved in tissue damage and premature cell aging. An increased amount of senescent cells in different tissues and organs has been found in experimental models of T2DM and obesity [2]. Senescent cells could participate in the onset and progression of multiple pathologies present in patients with T2DM. Their pro-inflammatory secretory phenotype supports the spreading of senescence, which contributes to the further progression of the related diseases [2,3,4]

Methods

Results

Conclusion