Nitric oxide directly promotes vascular endothelial insulin transport
Open accessAbstract
Insulin resistance strongly associates with decreased nitric oxide (NO) bioavailability and endothelial dysfunction. In the vasculature, NO mediates multiple processes that affect insulin delivery, including dilating both resistance and terminal arterioles in skeletal muscle in vivo. However, whether NO directly regulates vascular endothelial cell (EC) insulin uptake and its transendothelial transport (TET) is unknown. We report in this article that L-N(G)-nitro-L-arginine methyl ester (L-NAME) pretreatment blocked, whereas L-arginine and sodium nitroprusside (SNP) each enhanced, EC uptake of fluorescein isothiocyanate (FITC)-labeled insulin. SNP also partly or fully reversed the inhibition of EC insulin uptake caused by L-NAME, wortmannin, the Src inhibitor PP1, and tumor necrosis factor-α. In addition, SNP promoted [(125)I]Tyr(A14)insulin TET by ~40%. Treatment with insulin with and without SNP did not affect EC cyclic guanosine monophosphate (cGMP) levels, and the cGMP analog 8-bromo-cGMP did not affect FITC-insulin uptake. In contrast, treatment with insulin and SNP significantly increased EC protein S-nitrosylation, the colocalization of S-nitrosothiol (S-NO) and protein-tyrosine phosphatase 1B (PTP1B), and Akt phosphorylation at Ser(473) and inhibited PTP1B activity. Moreover, a high-fat diet significantly inhibited EC insulin-stimulated Akt phosphorylation and FITC-insulin uptake that was partially reversed by SNP in rats. Finally, inhibition of S-nitrosylation by knockdown of thioredoxin-interacting protein completely eliminated SNP-enhanced FITC-insulin uptake. We conclude that NO directly promotes EC insulin transport by enhancing protein S-nitrosylation. NO also inhibits PTP1B activity, thereby enhancing insulin signaling.
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The insulin receptor shares a signaling pathway with eNOS activation to regulate postprandial blood flow and efficient nutrient disposition to peripheral tissues.
“The insulin receptor shares a signaling pathway with the activation of endothelial NOS (eNOS) [19,48,49,50,51,52] to regulate the postprandial blood flow and efficient nutrient disposition to peripheral tissues”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [52]
NO mediates S-nitrosylation of PTPB1 and enhances the effects of insulin.
“Wang et al., indicated that NO mediates the S-nitrosylation of protein-tyrosine phosphatase 1B (PTPB1) and enhances the effects of insulin [52].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [52]
Insulin-stimulated NO production results in capillary recruitment and increased blood flow in skeletal muscle, leading to efficient glucose disposal.
“insulin-stimulated NO production has physiological consequences resulting in capillary recruitment and increased blood flow in skeletal muscle, leading to efficient glucose disposal [52].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [52]
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- Authors
- Wang, H., Wang, A. X., Aylor, K., & Barrett, E. J.
- Affiliations
- University of Virginia Health System (US)
- Corresponding author
- Wang, Hong
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2013-11-16
- Volume
- 62
- Issue
- 12
- Pages
- 4030-4042
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3837040
- OpenAlex
- W2098805210
- Cited by
- 117
- References
- 42
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 8 · 2023: 6 · 2022: 11 · 2021: 7 · 2020: 2 · 2019: 4 · 2018: 7 · 2017: 10 · 2016: 11 · 2015: 16 · 2014: 13 · 2013: 4
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association (11-BS6)
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK057878, DK073059, R01DK057878)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- nitric oxide, S-nitrosylation, PTP1B, Akt phosphorylation, insulin signaling, sodium nitroprusside, L-NAME, wortmannin, protein phosphatase 1, TNF-α, TXNIP, high-fat diet, insulin resistance, endothelial dysfunction, cyclic GMP
- MeSH terms
- Animals, Aorta, Arginine, Cattle, Cells, Cultured, Endothelium, Vascular, Enzyme Inhibitors, Insulin, Male, Nitric Oxide, Nitroprusside, Phosphorylation, Rats, Sprague-Dawley, Nitric Oxide Synthase, NG-Nitroarginine Methyl Ester, Nitric Oxide Donors, Protein Transport, Endothelial Cells, Proto-Oncogene Proteins c-akt, Rats, Protein Tyrosine Phosphatase, Non-Receptor Type 1
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