Emergence of SGLT2 Inhibitors as Powerful Antioxidants in Human Diseases

Tsai, Kai-Fan; Chen, Yung‐Lung; Chiou, Terry Ting-Yu; Chu, Tian‐Huei; Li, Lung-Chih; Ng, Hwee-Yeong; Lee, Wen‐Chin; Lee, Chien-Te

doi:10.3390/antiox10081166

Cited by 64 publications

(43 citation statements)

References 208 publications

(278 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Despite these facts, the role of SGLT2i on local RAS modulation in the LV is still unclear. The intrarenal RAS suppression has been demonstrated in response to SGLT2 inhibition in experimental models of T2D [ 32 ] and may contribute to the reduction in cardiovascular complications [ 33 ]. Our data suggest that empagliflozin leads to beneficial LV remodeling through decreased gene expression of the RAS classical pathway (renin, Ace1, and Atr1), in contrast to their high expression in the HF-fed mice, complying with the increased BSP and the LV hypertrophy found.…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin Alleviates Left Ventricle Hypertrophy in High-Fat-Fed Mice by Modulating Renin Angiotensin Pathway

Cotrin

Souza

Petito-da-Silva

et al. 2022

J Renin Angiotensin Aldosterone Syst

View full text Add to dashboard Cite

Aims. The cardiobenefits of empagliflozin are multidimensional, and some mechanisms are still unclear. The aim of the present study was to evaluate the effect of treatment with empagliflozin on biometric parameters and gene expression in the local cardiac RAS, oxidative stress, and endoplasmic reticulum pathways in a mouse model. Main Methods. Forty male C57BL/6 mice were fed with control (C) or high-fat (HF) diets for 10 weeks. After that, the groups were redistributed according to the treatment with empagliflozin—CE or HFE. The empagliflozin was administered via food for 5 weeks (10 mg/kg/day). We performed biochemical analyses, blood pressure monitoring, oral glucose tolerance test, left ventricle (LV) stereology, RT-qPCR for genes related to classical and counterregulatory local RAS, oxidative stress, and endoplasmic reticulum stress. Key Findings. In comparison to HF, HFE decreased body mass and improved glucose intolerance and insulin resistance. The cardiac parameters were enhanced after treatment as expressed by decrease in plasma cholesterol, plasma uric acid, and systolic blood pressure. In addition, LV analysis showed that empagliflozin reduces cardiomyocyte area and LV thickness. The local RAS had less activity of the classical pathway and positive effects on the counterregulatory pathway. Empagliflozin treatment also decreased oxidative stress and endoplasmic reticulum stress-related genes. Significance. Our results suggests that empagliflozin modulates the local RAS pathway towards alleviation of oxidative stress and ER stress in the LV, which may be a route to its effects on improved cardiac remodeling.

show abstract

Section: Discussionmentioning

confidence: 99%

Empagliflozin Alleviates Left Ventricle Hypertrophy in High-Fat-Fed Mice by Modulating Renin Angiotensin Pathway

Cotrin

Souza

Petito-da-Silva

et al. 2022

J Renin Angiotensin Aldosterone Syst

View full text Add to dashboard Cite

show abstract

“…The beneficial effects of SGLT2i treatment emerged from the DAPA-Heart Failure (HF) trial, in which reduction of HF and mortality was independent of reduction of hemoglobin A1C, and also from use of SGLT2i in experimental models of HF, in which cardiac improvements were independent of diabetes/hyperglycemia [56,57]. Moreover, accumulating preclinical studies demonstrate the therapeutic benefits of SGLT2i as powerful antioxidants in human diseases [58]. Thus, we may re-conceptualize the role of SGLT2i as organ-protective agents, including the endocrine pancreas in this study, by promoting adaptive cellular reprogramming of stressed cells for survival and function [59,60].…”

Section: Plos Onementioning

confidence: 99%

SGLT2 inhibitors therapy protects glucotoxicity-induced β-cell failure in a mouse model of human KATP-induced diabetes through mitigation of oxidative and ER stress

et al. 2022

View full text Add to dashboard Cite

Progressive loss of pancreatic β-cell functional mass and anti-diabetic drug responsivity are classic findings in diabetes, frequently attributed to compensatory insulin hypersecretion and β-cell exhaustion. However, loss of β-cell mass and identity still occurs in mouse models of human KATP-gain-of-function induced Neonatal Diabetes Mellitus (NDM), in the absence of insulin secretion. Here we studied the temporal progression and mechanisms underlying glucotoxicity-induced loss of functional β-cell mass in NDM mice, and the effects of sodium-glucose transporter 2 inhibitors (SGLT2i) therapy. Upon tamoxifen induction of transgene expression, NDM mice rapidly developed severe diabetes followed by an unexpected loss of insulin content, decreased proinsulin processing and increased proinsulin at 2-weeks of diabetes. These early events were accompanied by a marked increase in β-cell oxidative and ER stress, without changes in islet cell identity. Strikingly, treatment with the SGLT2 inhibitor dapagliflozin restored insulin content, decreased proinsulin:insulin ratio and reduced oxidative and ER stress. However, despite reduction of blood glucose, dapagliflozin therapy was ineffective in restoring β-cell function in NDM mice when it was initiated at >40 days of diabetes, when loss of β-cell mass and identity had already occurred. Our data from mouse models demonstrate that: i) hyperglycemia per se, and not insulin hypersecretion, drives β-cell failure in diabetes, ii) recovery of β-cell function by SGLT2 inhibitors is potentially through reduction of oxidative and ER stress, iii) SGLT2 inhibitors revert/prevent β-cell failure when used in early stages of diabetes, but not when loss of β-cell mass/identity already occurred, iv) common execution pathways may underlie loss and recovery of β-cell function in different forms of diabetes. These results may have important clinical implications for optimal therapeutic interventions in individuals with diabetes, particularly for those with long-standing diabetes.

show abstract

“…The SGLT2 inhibitors approved by the FDA, European Medicines Agency (EMA), Japan Pharmaceuticals and Medical Devices Agency (PMDA), and similar bureau in other countries include empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, luseogliflozin, and remogliflozin [ 158 ]. The general structure of this class of drugs is relatively similar and falls into the C-glucoside classification of the SGLT2 inhibitors with a glucose sugar and an aromatic group in the β-position at the anomeric carbon [ 159 , 160 ]. Below, we will summarize the most studied SGLT2 inhibitors, including the first found naturally occurring phloridzin as well as the pharmaceutical empagliflozin, ipragliflozin, canagliflozin, and dapagliflozin ( Figure 4 ).…”

Section: Sglt2 Inhibitors and Pdmentioning

confidence: 99%

Two Birds One Stone: The Neuroprotective Effect of Antidiabetic Agents on Parkinson Disease—Focus on Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

et al. 2021

View full text Add to dashboard Cite

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease affecting more than 1% of the population over 65 years old. The etiology of the disease is unknown and there are only symptomatic managements available with no known disease-modifying treatment. Aging, genes, and environmental factors contribute to PD development and key players involved in the pathophysiology of the disease include oxidative stress, mitochondrial dysfunction, autophagic–lysosomal imbalance, and neuroinflammation. Recent epidemiology studies have shown that type-2 diabetes (T2DM) not only increased the risk for PD, but also is associated with PD clinical severity. A higher rate of insulin resistance has been reported in PD patients and is suggested to be a pathologic driver in this disease. Oral diabetic drugs including sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to provide neuroprotective effects in both PD patients and experimental models; additionally, antidiabetic drugs have been demonstrated to lower incidence rates of PD in DM patients. Among these, the most recently developed drugs, SGLT2 inhibitors may provide neuroprotective effects through improving mitochondrial function and antioxidative effects. In this article, we will discuss the involvement of mitochondrial-related oxidative stress in the development of PD and potential benefits provided by antidiabetic agents especially focusing on sglt2 inhibitors.

show abstract

Emergence of SGLT2 Inhibitors as Powerful Antioxidants in Human Diseases

Cited by 64 publications

References 208 publications

Empagliflozin Alleviates Left Ventricle Hypertrophy in High-Fat-Fed Mice by Modulating Renin Angiotensin Pathway

Empagliflozin Alleviates Left Ventricle Hypertrophy in High-Fat-Fed Mice by Modulating Renin Angiotensin Pathway

SGLT2 inhibitors therapy protects glucotoxicity-induced β-cell failure in a mouse model of human KATP-induced diabetes through mitigation of oxidative and ER stress

Two Birds One Stone: The Neuroprotective Effect of Antidiabetic Agents on Parkinson Disease—Focus on Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors

Contact Info

Product

Resources

About