Empagliflozin protects heart from inflammation and energy depletion via AMPK activation

Koyani, Chintan N.; Plastira, Ioanna; Sourij, Harald; Hallström, Seth; Schmidt, Albrecht; Rainer, Peter P.; Bugger, Heiko; Frank, Saša; Malle, Ernst; Lewinski, Dirk von

doi:10.1016/j.phrs.2020.104870

Cited by 136 publications

(97 citation statements)

References 45 publications

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“…We hypothesized that empagliflozin treatment led to the activation of AMPK, thereby stabilizing TET2 and increasing its intracellular level. To test this hypothesis, we treated steatotic hepatocytes with the AMPK activator AICAR or its inhibitor, Compound C. The reagent used for testing was consistent with other studies (Koyani et al, 2020;Wang et al, 2020). Similar to empagliflozin, AICAR significantly reduced hepatocellular lipid content; in contrast, Compound C exacerbated lipid accumulation in the hepatocyte steatosis model (Figure 4A,B).…”

Section: Empagliflozin Elevates Tet2 and Autophagy Through Ampkmentioning

confidence: 60%

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

Fang

et al. 2021

Front. Pharmacol.

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Background: Metabolic associated fatty liver disease (MAFLD), characterized by hepatic lipid accumulation and fatty degeneration, is intertwined with obesity and type 2 diabetes mellitus (T2DM). Empagliflozin is a sodium-glucose cotransporter-2 inhibitor that effectively lowers blood glucose, but its effect on MAFLD and associated mechanisms are not fully understood.Methods: Eight-week-old db/db mice, an in vivo model, were administered empagliflozin or saline intragastrically. A hepatocyte steatosis model was established by inducing HL7702 cells with high glucose and palmitic acid and then treated with or without empagliflozin. The autophagy inhibitor (3-methyladenine, 3-MA) and AMP-activated protein kinase (AMPK) activator (AICAR)/inhibitor (Compound C) were used to determine the involvement of AMPK and autophagy in the regulation of lipid accumulation by empagliflozin. Ten-eleven translocation 2 (TET2) knockdown was achieved by siRNA transfection. Hepatic steatosis was evaluated by Oil Red O staining and triglyceride quantification. Immunohistochemistry, immunofluorescence, and western blot were performed to assess protein levels.Results: Empagliflozin alleviated liver steatosis in db/db mice and reduced triglyceride content and lipid accumulation in the hepatocyte steatosis model. Empagliflozin elevated autophagy, accompanied by an increase in p-AMPK and TET2. Both 3-MA and Compound C abolished the ability of empagliflozin to induce autophagy and reduce hepatic steatosis, while these effects could be recapitulated by AICAR treatment. TET2 knockdown resulted in autophagy inhibition and lipid accumulation despite empagliflozin treatment.Conclusion: Empagliflozin improves hepatic steatosis through the AMPK-TET2-autophagy pathway. The use of empagliflozin as a treatment for preventing and treating MAFLD in patients with T2DM warrants further study.

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Section: Empagliflozin Elevates Tet2 and Autophagy Through Ampkmentioning

confidence: 60%

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

Fang

et al. 2021

Front. Pharmacol.

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“…For SGLT2i, suggested mechanisms include (but are not limited to): reduced levels of plasma plasminogen activator inhibitor-1 (PAI-1), leading to visceral fat area loss and a restored adipokine balance [52]; beneficial vascular effects via anti-inflammatory mechanisms, as indicated by reduced high-sensitivity c-reactive protein (hs-CRP) [53]; energy repletion and reduced inflammation mediated by AMPK, together with reduced autophagy and lower levels of CD36 and cardiotoxic lipids, in the heart [54,55]; haemodynamic volume effects [56]; improved cardiac remodelling, increased provascular progenitor cells and decreased ischaemia/ reperfusion injury [57]; and off-target inhibition of the cardiac Na + /H + exchanger [58].…”

Section: Why Do Some Sglt2i and Glp-1 Ra Show Cardiorenal Benefits Inmentioning

confidence: 99%

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Schernthaner

Shehadeh

Аметов

et al. 2020

Cardiovasc Diabetol

109

108

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The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium–glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.

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“…Our data con rm that empagli ozin treatment reduces HOMA-IR, as described previously [23], which would improve insulin resistance. In line with a bene cial effect of empagli ozin, the drug has recently been reported to protect the heart from in ammation and energy depletion via AMPK activation [24], as well as preventing doxorubicin-induced myocardial dysfunction [25].…”

Section: Discussionmentioning

confidence: 92%

Empagliflozin Ameliorates Leukocyte – Endothelium Cell Interactions and Inflammation in Type 2 Diabetic Patients

Iannantuoni¹,

Canet²,

López‐Domènech³

et al. 2020

Preprint

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Abstract Background: SGLT2 inhibitors (iSGLT2) such as empagliflozin can reduce cardiovascular risk in patients with type 2 diabetes, but the underlying molecular mechanisms are yet to be determined. In the present study we evaluate the effects of empagliflozin on anthropometric and endocrine parameters, leukocyte-endothelium interactions, adhesion molecules and NFkB-p65 transcription factor expression. Methods: Eighteen patients with type 2 diabetes were recruited for the study. Patients received 10 mg/day of empagliflozin according to standard clinical protocols and were followed-up during a 24-week period. Anthropometric and analytical measurements were performed at baseline, 12-weeks and 24-weeks. Interactions between polymorphonuclear leukocytes and human umbilical vein endothelial cells (HUVECs), serum levels of adhesion molecules (P-selectin, VCAM-1 and ICAM-1) and NFkB-p65 protein levels were measured. Results: We observed a decrease in body weight, BMI and HbA1C levels from 12 weeks of treatment, which had become more pronounced at 24 weeks and was accompanied by a significant reduction in waist circumference, glucose, and hs-CRP levels. Leukocyte-endothelium interactions were reduced due to an enhancement of leukocyte rolling velocity from 12 weeks onwards, together with a significant decrease in leukocyte rolling flux and adhesion at 24 weeks. Accordingly, a significant decrease in ICAM-1 levels and NFkB-p65 expression were observed. Conclusions: Empagliflozin reduced leukocyte-endothelium interactions, adhesion molecules and NFkB-p65 expression in type 2 diabetic patients after 24 weeks of treatment.

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Empagliflozin protects heart from inflammation and energy depletion via AMPK activation

Cited by 136 publications

References 45 publications

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

Empagliflozin Alleviates Hepatic Steatosis by Activating the AMPK-TET2-Autophagy Pathway in vivo and in vitro

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes

Empagliflozin Ameliorates Leukocyte – Endothelium Cell Interactions and Inflammation in Type 2 Diabetic Patients

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