Minimizing Hyperglycemia-Induced Vascular Endothelial Dysfunction by Inhibiting Endothelial Sodium-Glucose Cotransporter 2 and Attenuating Oxidative Stress

Implications for Treating Individuals With Type 2 Diabetes

Vivek Krishna Pulakazhi Venu, Mahmoud El-Daly, Mahmoud Saifeddine, Simon A. Hirota, Hong Ding, Christopher Triggle, Morley D. Hollenberg

Research output: Contribution to journalArticle

Abstract

This overview deals with mechanisms whereby hyperglycemia-induced oxidative stress compromises vascular endothelial function and provides a background for a recently published study illustrating the beneficial impact of endothelial sodium-glucose cotransporter 2 (SGLT2) inhibitors in attenuating hyperglycemia-induced vascular dysfunction in vitro. The data provide new insight that can possibly lead to improved drug therapy for people with type 2 diabetes. The working hypotheses that underpinned the experiments performed are provided, along with the findings of the study. For the causes of hyperglycemia-induced vascular endothelial dysfunction, the findings point to the key roles of: 1) functional endothelial SGLT2; 2) oxidative stress-induced signalling pathways including mammalian sarcoma virus kinase, the EGF receptor-kinase and protein kinase C; and 3) mitochondrial dysfunction triggered by hyperglycemia was mitigated by an SGLT2 inhibitor in the hyperglycemic mouse aorta vascular organ cultures. The overview sums up the approaches implicated by the study that can potentially counteract the detrimental impact of hyperglycemia on vascular function in people with diabetes, including the clinical use of SGLT2 inhibitors for those with type 2 diabetes already being treated, for example, with metformin, along with dietary supplementation with broccoli-derived sulforaphane and tetrahydrobiopterin. The caveats associated with the study for extending the findings from mice to humans are summarized, pointing to the need to validate the work using vascular tissues from humans. Suggestions for future clinical studies are made, including the assessment of the impact of the therapeutic strategies proposed on measurements of blood flow in subjects with diabetes.

Original languageEnglish
JournalCanadian Journal of Diabetes
DOIs
Publication statusPublished - 1 Jan 2019

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Sodium-Glucose Transport Proteins
Hyperglycemia
Type 2 Diabetes Mellitus
Blood Vessels
Oxidative Stress
Obese Mice
Metformin
Brassica
Organ Culture Techniques
Dietary Supplements
Epidermal Growth Factor Receptor
Sarcoma
Aorta
Phosphotransferases
Viruses
Drug Therapy

Keywords

  • dysfonctionnement de l'endothélium
  • endothelial dysfunction
  • hyperglycemia
  • hyperglycémie
  • inhibiteurs du SGLT2
  • oxidative stress
  • SGLT2 inhibitors
  • stress oxydatif
  • sulforaphane
  • sulforaphane
  • tetrahydrobiopterin
  • tétrahydrobioptérine

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

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title = "Minimizing Hyperglycemia-Induced Vascular Endothelial Dysfunction by Inhibiting Endothelial Sodium-Glucose Cotransporter 2 and Attenuating Oxidative Stress: Implications for Treating Individuals With Type 2 Diabetes",
abstract = "This overview deals with mechanisms whereby hyperglycemia-induced oxidative stress compromises vascular endothelial function and provides a background for a recently published study illustrating the beneficial impact of endothelial sodium-glucose cotransporter 2 (SGLT2) inhibitors in attenuating hyperglycemia-induced vascular dysfunction in vitro. The data provide new insight that can possibly lead to improved drug therapy for people with type 2 diabetes. The working hypotheses that underpinned the experiments performed are provided, along with the findings of the study. For the causes of hyperglycemia-induced vascular endothelial dysfunction, the findings point to the key roles of: 1) functional endothelial SGLT2; 2) oxidative stress-induced signalling pathways including mammalian sarcoma virus kinase, the EGF receptor-kinase and protein kinase C; and 3) mitochondrial dysfunction triggered by hyperglycemia was mitigated by an SGLT2 inhibitor in the hyperglycemic mouse aorta vascular organ cultures. The overview sums up the approaches implicated by the study that can potentially counteract the detrimental impact of hyperglycemia on vascular function in people with diabetes, including the clinical use of SGLT2 inhibitors for those with type 2 diabetes already being treated, for example, with metformin, along with dietary supplementation with broccoli-derived sulforaphane and tetrahydrobiopterin. The caveats associated with the study for extending the findings from mice to humans are summarized, pointing to the need to validate the work using vascular tissues from humans. Suggestions for future clinical studies are made, including the assessment of the impact of the therapeutic strategies proposed on measurements of blood flow in subjects with diabetes.",
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author = "{Pulakazhi Venu}, {Vivek Krishna} and Mahmoud El-Daly and Mahmoud Saifeddine and Hirota, {Simon A.} and Hong Ding and Christopher Triggle and Hollenberg, {Morley D.}",
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AU - Saifeddine, Mahmoud

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AU - Ding, Hong

AU - Triggle, Christopher

AU - Hollenberg, Morley D.

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