Post-challenge hyperglycaemia, nitric oxide production and endothelial dysfunction: the putative role of asymmetric dimethylarginine (ADMA).
Open accessAbstract
The endothelium is a thin layer of cells at the internal surface of blood vessels in continuous contact with the circulating fluids. The endothelial cells represent the primary barrier for the transport of glucose from the vascular conduits into the interstitial space. Insulin and nitric oxide have an important role in the regulation of glucose transport and metabolism. Hyperglycaemia is the main criteria for the diagnosis of diabetes and is responsible for the micro- and macro-vascular pathology seen in diabetic patients. Recent evidence suggests that post-challenge hyperglycaemia is a better predictor of cardiovascular risk than fasting glucose. Acute glucose elevations have been associated with a reduced endothelial-dependent flow mediated dilation indicating a decrease in nitric oxide production. Post-prandial hyperglycaemic peaks have been directly associated with increased intima media thickness in type 2 diabetic patients indicative of an increased atherosclerotic risk. The increase in intra-cellular glucose concentrations in the endothelial cells induces a hyper-generation of reactive oxygen species via the activation of different pathways (polyol-sorbitol, hexosamine, advanced glycated end products, activation of PKC, asymmetric dimethylarginine (ADMA)). These mechanisms influence the expression of genes and release of signalling and structural molecules involved in several functions (inflammation, angiogenesis, coagulation, vascular tone and permeability, cellular migration, nutrient metabolism). ADMA is considered as a biomarker of endothelial dysfunction and it has been associated with an increased risk of atherosclerosis and cardiovascular diseases. The increased generation of ADMA and reactive oxygen species in subjects with persistent hyperglycaemia could lead to an impairment of nitric oxide synthesis.
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Lower nitric oxide availability has been linked to impaired endothelial function and higher risk of hypertension and cardiovascular disease.
“Reduced NO bioavailability has been associated with impairment of endothelial function and increased risk of hypertension and cardiovascular diseases (17)(18)(19)(20).”
From Inorganic Nitrate and Beetroot Juice Supplementation Reduces Blood Pressure in Adults: A Systematic Review and Meta-Analysis (2013) · cites this paper as [19]
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Endothelial Dysfunction and Hypertension
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Sugar consumption and global prevalence of obesity and hypertension: an ecological analysis
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The role of oxidative stress in postprandial endothelial dysfunction
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Hussin, A. M., Ashor, A. W., Schoenmakers, I., Hill, T. R., Mathers, J. C., & Siervo, M. (2016) · European Journal of Nutrition · doi:10.1007/s00394-016-1159-3 · Cited by 52 · see citing works
Doğru, T., Genç, H., Tapan, S., Erçin, C. N., Örs, F., Aslan, F., Kara, M., Sertoğlu, E., Bağcı, S., Kurt, İ., et al. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.11.022 · Cited by 51 · see citing works
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Microvascular dysfunction and efficacy of PDE5 inhibitors in BPH–LUTS
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MicroRNA21 promotes interstitial fibrosis via targeting DDAH1: a potential role in renal fibrosis
Liu, X., Hong, Q., Wang, Z., Yu, Y., Zou, X., & Xu, L. (2015) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-015-2580-2 · Cited by 40 · see citing works
Retnakaran, R. R., Qi, Y., Sermer, M., Connelly, P. W., Hanley, A. J., & Zinman, B. (2011) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2011.02.010 · Cited by 28 · see citing works
Siervo, M., & Bluck, L. (2012) · Metabolism: Clinical and Experimental · doi:10.1016/j.metabol.2011.10.003 · Cited by 26 · see citing works
Hu, Y., Gu, X., Zhang, Y., Ma, W., Sun, L., Wang, C., & Ren, B. (2023) · Environmental Toxicology · doi:10.1002/tox.23958 · Cited by 22 · see citing works
Boğa, S., Alkım, H., Köksal, A. R., Bayram, M., Ozguven, M. B. Y., Ergün, M., Neijmann, S. T., Ozgon, G. O., & Alkım, C. (2015) · Journal of Investigative Medicine · doi:10.1097/jim.0000000000000230 · Cited by 21 · see citing works
Cardiovascular risk in autoimmune disorders: Role of asymmetric dimethylarginine
Chen, X.-M., Hu, C., Li, Y., & Jiang, J. (2012) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.09.019 · Cited by 21 · see citing works
Involvement of DDAH/ADMA pathway in the pathogenesis of rheumatoid arthritis in rats
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Atorvastatin protects endothelium by decreasing asymmetric dimethylarginine in dyslipidemia rats
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The Role of the NOS-ADMA-DDAH1 Pathway in Adipocytes and Obesity
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Adolphe, J. L. (2013) · HARVEST (University of Saskatchewan)
Sagar, P. S., Munt, A., Saravanabavan, S., Vahedi, F. A., Elhindi, J., Nguyen, B., Chau, K., Harris, D. C. H., Lee, V. W., Sud, K., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23803165
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Sagar, P. S., Munt, A., Saravanabavan, S., Vahedi, F. A., Elhindi, J., Nguyen, B., Chau, K., Harris, D. C. H., Lee, V. W., Sud, K., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23803162
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Endothelium—The regulator of atherosclerosis
Ning, K., Shao, C., Xue, W., Shen, Y., & Guo, H.-D. (2026) · Genes & Diseases · doi:10.1016/j.gendis.2026.102286
- Authors
- Siervo, M., Corander, M., Stranges, S., & Bluck, L.
- Affiliations
- MRC Elsie Widdowson Laboratory (GB)
- University of Cambridge (GB)
- University of Warwick (GB)
- Venue
- Nutrition Metabolism and Cardiovascular Diseases
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 21
- Issue
- 1
- Pages
- 1-10
- ISSN
- 0939-4753 (ISSN-L)
- OpenAlex
- W2029397220
- Cited by
- 55
- References
- 101
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 12 · 2022: 5 · 2020: 5 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 8 · 2014: 1 · 2013: 6 · 2012: 4
- FWCI
- 3.25
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nutrition Metabolism and Cardiovascular Diseases (publishedVersion)
- PubMed (publishedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- asymmetric dimethylarginine, endothelial dysfunction, nitric oxide production, reactive oxygen species, type 2 diabetes, postprandial blood glucose, flow-mediated dilation, atherosclerosis, cardiovascular risk, advanced glycation end products, polyol pathway, hexosamine biosynthetic pathway, protein kinase C
- MeSH terms
- Animals, Arginine, Diabetes Mellitus, Type 2, Endothelium, Vascular, Glucose, Glucose Tolerance Test, Heart Diseases, Humans, Hyperglycemia, Metabolic Diseases, Nitric Oxide, Oxidative Stress
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