Cited by 105Nitric Oxide and Endothelin EffectsMetabolism, Diabetes, and CancerNatural Antidiabetic Agents Studies

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Dietary nitrite improves insulin signaling through GLUT4 translocation

Jiang, Hong, Torregrossa, Ashley C., Potts, Amy, Pierini, Dan, Aranke, Mayank, Garg, Harsha K., Bryan, Nathan S.·2014·Free Radical Biology and Medicine

DOI 10.1016/j.freeradbiomed.2013.10.809

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Abstract

Diabetes mellitus type 2 is a syndrome of disordered metabolism with inappropriate hyperglycemia owing to a reduction in the biological effectiveness of insulin. Type 2 diabetes is associated with an impaired nitric oxide (NO) pathway that probably serves as the key link between metabolic disorders and cardiovascular disease. Insulin-mediated translocation of GLUT4 involves the PI3K/Akt kinase signal cascade that results in activation of endothelial NO synthase (eNOS). eNOS is dysfunctional during diabetes. We hypothesize that loss of eNOS-derived NO terminates the signaling cascade and therefore cannot activate GLUT4 translocation and that dietary nitrite may repair this pathway. In this study, we administered 50mg/L sodium nitrite to db/db diabetic mice for 4 weeks. After 4 weeks treatment, the db/db mice experienced less weight gain, improved fasting glucose levels, and reduced insulin levels. Cell culture experiments using CHO-HIRc-myc-GLUT4eGFP cell lines stably expressing insulin receptor and myc-GLUT4eGFP protein, as well as L6 skeletal muscle cells stably expressing rat GLUT4 with a Myc epitope (L6-GLUT4myc), showed that NO, nitrite, and GSNO stimulate GLUT4 translocation independent of insulin, which is inhibited by NEM. Collectively our data suggest that nitrite improves insulin signaling through restoration of NO-dependent nitrosation of GLUT4 signaling translocation. These data suggest that NO-mediated nitrosation of GLUT4 by nitrite or other nitrosating agents is necessary and sufficient for GLUT4 translocation in target tissue. Description of this pathway may justify a high-nitrate/nitrite diet along with the glycemic index to provide a safe and nutritional regimen for the management and treatment of diabetes.

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Authors: Jiang, H., Torregrossa, A. C., Potts, A., Pierini, D., Aranke, M., Garg, H. K., & Bryan, N. S.
Affiliations: Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
California State University, Fullerton (US)
The University of Texas at Austin (US)
Corresponding author: Bryan, Nathan S.
ORCID: Jiang, Hong
Bryan, Nathan S.
Venue: Free Radical Biology and Medicine
Publisher: Elsevier BV
Published: 2014-02
Volume: 67
Pages: 51-57
ISSN: 0891-5849 (ISSN-L)
DOI: 10.1016/j.freeradbiomed.2013.10.809
OpenAlex: W2049215298
Cited by: 105
References: 45
Citations by year: 2026: 6 · 2025: 3 · 2024: 8 · 2023: 8 · 2022: 7 · 2021: 9 · 2020: 11 · 2019: 12 · 2018: 7 · 2017: 13 · 2016: 7 · 2015: 11 · 2014: 3
FWCI: 4.86
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Free Radical Biology and Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: University of Texas Health Science Center at Houston
Hospital for Sick Children
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords: dietary nitrite, sodium nitrite, insulin signaling, GLUT4 translocation, nitric oxide, type 2 diabetes, endothelial nitric oxide synthase, PI3K/Akt signaling, nitrosation, S-nitrosoglutathione, db/db mice, skeletal muscle, glycemic control
MeSH terms: Animals, Diabetes Mellitus, Type 2, Disease Models, Animal, Ethylmaleimide, Gene Expression Regulation, Humans, Male, Mice, Transgenic, Nitric Oxide, Receptor, Insulin, Sodium Nitrite, Signal Transduction, Proto-Oncogene Proteins c-myc, Protein Transport, Glucose Transporter Type 4, Mice, Rats, Nitric Oxide Synthase Type III

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Dietary nitrite improves insulin signaling through GLUT4 translocation

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