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The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats

Sebastian Steven1, Matthias Oelze2, Alina Hanf2

  • 1Center for Cardiology, Cardiology I - Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany; Center for Thrombosis and Hemostasis, Medical Center of the Johannes Gutenberg University, Mainz, Germany, Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Redox Biology
|July 2, 2017
PubMed

Insights

Empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i), improved glycemic control and reduced cardiovascular risks in diabetic rats. It mitigated inflammation, oxidative stress, and endothelial dysfunction, suggesting a protective mechanism against diabetes complications.

Area of Science:

  • Cardiovascular Pharmacology
  • Metabolic Disease Research
  • Diabetes Mellitus Pathophysiology

Background:

  • Hyperglycemia in diabetes mellitus drives inflammation, oxidative stress, and vascular dysfunction, contributing to cardiovascular disease.
  • Selective sodium-glucose co-transporter 2 inhibitors (SGLT2i), like empagliflozin, reduce hyperglycemia by promoting urinary glucose excretion and have shown cardiovascular benefits in type 2 diabetes mellitus (T2DM).

Purpose of the Study:

  • To investigate the effects of empagliflozin on glucotoxicity, beta-cell function, inflammation, oxidative stress, and endothelial dysfunction in Zucker diabetic fatty (ZDF) rats, a model for T2DM.
  • To explore the underlying mechanisms by which empagliflozin may prevent cardiovascular complications associated with diabetes.

Main Methods:

  • Male ZDF rats (diabetic and control groups) were treated with empagliflozin (10 and 30mg/kg/d) for 6 weeks.
  • Assessed glycemic control (HbA1c), endothelial function (thoracic aorta), oxidative stress markers, inflammation (C-reactive protein), and AGE/RAGE signaling.
  • Utilized chromatin immunoprecipitation (ChIP) for epigenetic analysis and linear regression to correlate markers with endothelial function.

Main Results:

  • Empagliflozin treatment restored glycemic control in ZDF rats.
  • Significant improvements in endothelial function and reductions in oxidative stress and inflammation were observed in empagliflozin-treated rats.
  • Glucotoxicity and AGE/RAGE signaling were epigenetically mitigated, and endothelial cell viability improved.

Conclusions:

  • Empagliflozin effectively reduces glucotoxicity, oxidative stress, and inflammation in a preclinical T2DM model.
  • These findings support the hypothesis that empagliflozin's cardiovascular benefits stem from ameliorating hyperglycemia-induced damage, independent of lipid and insulin levels.
  • Preclinical data provide mechanistic insights into empagliflozin's role in reducing cardiovascular mortality in T2DM patients.
Keywords:
AGE/RAGE signalingDiabetesEndothelial dysfunctionLow-grade inflammationOxidative stressSGLT2 inhibitorZucker diabetic fatty ratsβ-cell content

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