Sodium–glucose cotransporter inhibitors and oxidative stress: An update

Yaribeygi, Habib; Atkin, Stephen L.; Butler, Alexandra E.; Sahebkar, Amirhossein

doi:10.1002/jcp.26760

Cited by 121 publications

(77 citation statements)

References 76 publications

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“…As such, we propose that hyperglycemia-glucotoxicity associated with diabetes in the db / db female promotes the glucose-oxidative stress pathway via increased generation of reactive oxygen–nitrogen species (ROS/RNS) [3,8,9,10,12,22] (Figure 14). On the other hand, there are multiple situations that may, in part, contribute to the ultrastructural remodeling mechanisms from clinical scenarios as follows: aging, lifestyle, environment, genetics—particularly the leptin receptor deficiencies in the DBC and also the potentially numerous single-nucleotide polymorphisms (SNPs) in humans, and comorbidities associated with obesity (metabolic syndrome and accelerated atherosclerosis) [3].…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin Ameliorates Type 2 Diabetes-Induced Ultrastructural Remodeling of the Neurovascular Unit and Neuroglia in the Female db/db Mouse

et al. 2019

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Type 2 diabetes is associated with diabetic cognopathy. Anti-hyperglycemic sodium glucose transporter 2 (SGLT2) inhibitors have shown promise in reducing cognitive impairment in mice with type 2 diabetes mellitus. We recently described marked ultrastructural (US) remodeling of the neurovascular unit (NVU) in type 2 diabetic db/db female mice. Herein, we tested whether the SGLT-2 inhibitor, empagliflozin (EMPA), protects the NVU from abnormal remodeling in cortical gray and subcortical white matter. Ten-week-old female wild-type and db/db mice were divided into lean controls (CKC, n = 3), untreated db/db (DBC, n = 3), and EMPA-treated db/db (DBE, n = 3). Empagliflozin was added to mouse chow to deliver 10 mg kg−1 day−1 and fed for ten weeks, initiated at 10 weeks of age. Brains from 20-week-old mice were immediately immersion fixed for transmission electron microscopic study. Compared to CKC, DBC exhibited US abnormalities characterized by mural endothelial cell tight and adherens junction attenuation and/or loss, pericyte attenuation and/or loss, basement membrane thickening, glia astrocyte activation with detachment and retraction from mural cells, microglia cell activation with aberrant mitochondria, and oligodendrocyte–myelin splitting, disarray, and axonal collapse. We conclude that these abnormalities in the NVU were prevented in DBE. Empagliflozin may provide neuroprotection in the diabetic brain.

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Section: Discussionmentioning

confidence: 99%

Empagliflozin Ameliorates Type 2 Diabetes-Induced Ultrastructural Remodeling of the Neurovascular Unit and Neuroglia in the Female db/db Mouse

et al. 2019

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“…A recent study demonstrated an improved arterial stiffness after 6 weeks of treatment with empagliflozin in T2D patients, and hs-CRP was shown to be one of the main significant determinants for this improvement [29]. Nevertheless, despite the available evidence, the molecular mechanisms underlying the cardiovascular protection attributable to iSGLT2 treatment are still unknown, though amelioration of oxidative stress has been hypothesized to be a potential contributor [30]. Because cardiac tissue possesses low antioxidant defenses, increasing the expression or activity of antioxidant enzymes could be a mechanism of cardiac protection under high risk situations such as T2D.…”

Section: Discussionmentioning

confidence: 99%

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

Iannantuoni

Marañón

Díaz-Morales

et al. 2019

JCM

113

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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.

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“…SGLT2is can reduce systemic and tissue low-grade inflammation [44][45][46] as well as oxidative stress 164 . While these conditions aggravate vascular complications in patients with T2DM, it is unknown what might be the contribution of these effects on the cardiovascular and renal protection reported with SGLT2is.…”

Section: Effects On Low-grade Inflammationmentioning

confidence: 99%

Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus

2020

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The management of type 2 diabetes mellitus (T2DM) is becoming increasingly complex. Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are the newest antidiabetic agents for T2DM. By targeting the kidney, they have a unique mechanism of action, which results in enhanced glucosuria, osmotic diuresis and natriuresis, thereby improving glucose control with a limited risk of hypoglycaemia and exerting additional positive effects such as weight loss and the lowering of blood pressure. Several outcome studies with canagliflozin, dapagliflozin or empagliflozin reported a statistically significant reduction in major cardiovascular events, hospitalization for heart failure and progression to advanced renal disease in patients with T2DM who have established atherosclerotic cardiovascular disease, several cardiovascular risk factors, albuminuric mild to moderate chronic kidney disease or heart failure. Current guidelines proposed a new paradigm in the management of T2DM, with a preferential place for SGLT2is, after metformin, in patients with atherosclerotic cardiovascular disease, heart failure and progressive kidney disease. Ongoing trials might extend the therapeutic potential of SGLT2is in patients with, but also without, T2DM. This Review provides an update of the current knowledge on SGLT2is, moving from their use as glucose-lowering medications to their new positioning as cardiovascular and renal protective agents.

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Sodium–glucose cotransporter inhibitors and oxidative stress: An update

Cited by 121 publications

References 76 publications

Empagliflozin Ameliorates Type 2 Diabetes-Induced Ultrastructural Remodeling of the Neurovascular Unit and Neuroglia in the Female db/db Mouse

Empagliflozin Ameliorates Type 2 Diabetes-Induced Ultrastructural Remodeling of the Neurovascular Unit and Neuroglia in the Female db/db Mouse

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

Sodium–glucose cotransporter type 2 inhibitors for the treatment of type 2 diabetes mellitus

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