The SGLT2 Inhibitor Empagliflozin Ameliorates the Inflammatory Profile in Type 2 Diabetic Patients and Promotes an Antioxidant Response in Leukocytes

Francesca Iannantuoni, Aranzazu M de Marañon, Noelia Diaz-Morales, Rosa Falcon, Celia Bañuls, Zaida Abad-Jimenez, Victor M Victor, Antonio Hernandez-Mijares, Susana Rovira-Llopis, Francesca Iannantuoni, Aranzazu M de Marañon, Noelia Diaz-Morales, Rosa Falcon, Celia Bañuls, Zaida Abad-Jimenez, Victor M Victor, Antonio Hernandez-Mijares, Susana Rovira-Llopis

Abstract

Sodium-glucose co-transporter 2 inhibitors (iSGLT2) have been linked to a considerable reduction in cardiovascular risk in patients with type 2 diabetes (T2D), but the precise molecular mechanisms are still elusive. We aimed to evaluate the effects of the iSGLT2 empagliflozin on systemic inflammation and its potential antioxidant properties. This is an observational, prospective follow-up study of a cohort of fifteen patients with T2D who received 10 mg/day of empagliflozin according to standard clinical care. Measures at baseline, 12 and 24 weeks were taken. Metabolic and anthropometric parameters were evaluated. Production of mitochondrial superoxide, glutathione content, and glutathione s-reductase and catalase mRNA levels were measured in leukocytes. Serum levels of myeloperoxidase, hs-CRP and IL-10 were determined. In addition to decreased body weight and reduced glucose and HbA1c levels, we observed a reduction in superoxide production in leukocytes of diabetic patients and increased glutathione content, prominently after 24 weeks of empagliflozin treatment. Leukocyte expression of glutathione s-reductase and catalase, and serum levels of IL-10 were enhanced at 24 weeks of empagliflozin treatment. Concomitantly, reduced hs-CRP and myeloperoxidase levels were seen. This study provides evidence of the antioxidant and anti-inflammatory properties of empagliflozin treatment in humans, which may contribute to its beneficial cardiovascular effects.

Keywords: SGLT2 inhibitors; empagliflozin; inflammation; leukocytes; oxidative stress; type 2 diabetes.

Conflict of interest statement

The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Empagliflozin effect on glucose metabolism. Blood glucose (A) and HbA1c levels (B) at 12 and at 24 weeks of treatment with empagliflozin 10 mg/day. Abbreviations: EMPA, empagliflozin; HbA1c %, glycated hemoglobin. * p < 0.05 vs. type 2 diabetes baseline.
Figure 2
Figure 2
Effect of empagliflozin treatment on oxidative stress parameters and antioxidant enzymes. Mitochondrial superoxide production (A), GSH content (B) and mRNA expression of the antioxidant enzymes GSR (C) and CAT (D) in human leukocytes at 12 and 24 weeks of empagliflozin treatment. Data were normalized to fluorescence at baseline. The values of the relative gene expression were normalized to baseline mRNA expression levels and calculated using the 2−ΔΔCT method. Abbreviations: EMPA, empagliflozin; MTX, MitoSOX Red mitochondrial superoxide indicator; CMFDA, 5-chloromethylfluorescein diacetate; GSH, glutathione, GSR, glutathione S-reductase; CAT, catalase. * p < 0.05, ** p < 0.05 vs. type 2 diabetes baseline. Representative fluorescence microscopy images are shown.
Figure 3
Figure 3
Assessment of inflammatory parameters; serum hs-CRP (A), MPO (B) and IL-10 (C) levels at baseline, 12 and 24 weeks of treatment. Abbreviations: EMPA, empagliflozin; hs-CRP, high-sensitive C-reactive protein; MPO, myeloperoxidase; IL-10, interleukin 10. * p < 0.05 compared with type 2 diabetes baseline.

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