Endothelial Dysfunction and Low-Grade Inflammation Explain Much of the Excess Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Hoorn Study

de Jager, Jolien; Dekker, Jacqueline M.; Kooy, Adriaan; Kostense, Piet J.; Nijpels, Giel; Heine, Rob J.; Bouter, Lex M.; Stehouwer, Coen D.A.

doi:10.1161/01.atv.0000215951.36219.a4

Cited by 164Diabetes, Cardiovascular Risks, and LipoproteinsNitric Oxide and Endothelin EffectsAdipokines, Inflammation, and Metabolic Diseases

Endothelial Dysfunction and Low-Grade Inflammation Explain Much of the Excess Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Hoorn Study

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de Jager, Jolien, Dekker, Jacqueline M., Kooy, Adriaan, Kostense, Piet J., Nijpels, Giel, Heine, Rob J., Bouter, Lex M., Stehouwer, Coen D.A.·2006·Arteriosclerosis, Thrombosis, and Vascular Biology

DOI 10.1161/01.atv.0000215951.36219.a4

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Abstract

Objective— The mechanisms responsible for the increased cardiovascular disease risk that accompanies type 2 diabetes (T2D) remain poorly understood. It is commonly held that endothelial dysfunction and low-grade inflammation can explain, at least in part, why deteriorating glucose tolerance is associated with cardiovascular disease. However, there is no direct evidence for this contention. Methods and Results— In this population-based study (n=631), T2D was cross-sectionally associated with both endothelial dysfunction and low-grade inflammation, whereas impaired glucose metabolism (IGM) was associated only with low-grade inflammation. These findings were independent of other risk factors that accompany T2D or IGM. During a follow-up of 11.7 years (median; range 0.5 to 13.2 years), low-grade inflammation was associated with a greater risk of cardiovascular mortality (hazard ratio, 1.43 [95% CI, 1.17 to 1.77] per 1 SD difference). For endothelial dysfunction, the association with cardiovascular mortality was stronger in diabetic (hazard ratio, 1.87 [95% CI, 1.43 to 2.45]) than in nondiabetic individuals (hazard ratio, 1.23 [95% CI, 0.86 to 1.75]; P interaction=0.06). Finally, T2D-associated endothelial dysfunction and low-grade inflammation explained ≈43% of the increase in cardiovascular mortality risk conferred by T2D. Conclusions— These data emphasize the necessity of randomized controlled trials of strategies that aim to decrease cardiovascular disease risk by improving endothelial function and decreasing low-grade inflammation, especially for T2D patients.

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T2DM is associated with low-grade inflammation, cardiovascular disease, nephropathy and alterations in secretion of various hormones including IL-6, IL-18, TNF-α, adiponectin, leptin, neuropeptides, ghrelin, and incretins GLP-1 and GIP.
“Furthermore, T2DM is associated with low-grade inflammation,382, 383 cardiovascular disease,384, 385 nephropathy386, 387 and alterations in the secretion of various hormones, including IL-6, IL-18, tumor necrosis factor-α,388 adiponectin and leptin,389 neuropeptides,390 ghrelin391, 392 and the incretins GLP-1 and GIP.219, 220, 221, 222, 223”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [383]

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Endothelial dysfunction and low-grade inflammation explain much of the excess cardiovascular mortality in individuals with type 2 diabetes The Hoorn
de Jager, J., Dekker, J. M., Kooy, A., Kostense, P. J., Nijpels, G., Heine, R. J., Bouter, L. M., & Stehouwer, C. D. A. (2016)
Self-citation
Endothelial Dysfunction Plays a Key Role in Increasing Cardiovascular Risk in Type 2 Diabetes
van Sloten, T. T., Henry, R. M. A., Dekker, J. M., Nijpels, G., Unger, T., Schram, M. T., & Stehouwer, C. D. A. (2014) · Hypertension · doi:10.1161/hypertensionaha.114.04221 · Cited by 114 · see citing works
Self-citation
Additive Prognostic Importance of Low-Grade Inflammation for Major Cardiovascular Events and Mortality in Recently Diagnosed Type 2 Diabetes without Prevalent Cardiovascular Disease: A Nationwide Danish Cohort StudyPreprint
Domazet, S. L., Sharfo, A., Olesen, T., Stidsen, J. V., Nielsen, J. S., Thomsen, R. W., Jessen, N., Vestergaard, P., Andersen, M. K., Hansen, T. F., et al. (2025) · SSRN Electronic Journal · doi:10.2139/ssrn.5640937
Low-grade inflammation as a risk factor for cardiovascular events and all-cause mortality in patients with type 2 diabetes
Sharif, S., Van der Graaf, Y., Cramer, M. J., Kapelle, L. J., de Borst, G. J., Visseren, F. L. J., Westerink, J., the SMART study group, van Petersen, R., Dinther, B. G. F., et al. (2021) · Cardiovascular Diabetology · doi:10.1186/s12933-021-01409-0 · Cited by 198 · see citing works
Endothelial Dysfunction in Diabetes
Chandel, S., Tiwari, R. K., & Dixit, M. (2017) · Springer eBooks · doi:10.1007/978-3-319-60324-7_5 · Cited by 1 · see citing works

Authors: de Jager, J., Dekker, J. M., Kooy, A., Kostense, P. J., Nijpels, G., Heine, R. J., Bouter, L. M., & Stehouwer, C. D. A.
Affiliations: From the Department of Internal Medicine, Bethesda General Hospital, Hoogeveen, the Netherlands (J.d.J., A.K); the Institute for Research in Extramural Medicine (J.M.D., P.J.K., G.N., R.J.H., L.M.B., C.D.A.S.), VU University Medical Center, Amsterdam, The Netherlands; and the Department of Internal Medicine, University Hospital Maastricht, The Netherlands (C.D.A.S.).
Maastricht University Medical Centre (NL)
ORCID: Kooy, Adriaan
Nijpels, Giel
Bouter, Lex M.
Stehouwer, Coen D.A.
Venue: Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2006-05
Volume: 26
Issue: 5
Pages: 1086-1093
ISSN: 1079-5642 (ISSN-L)
1524-4636
DOI: 10.1161/01.atv.0000215951.36219.a4
OpenAlex: W2096259240
Cited by: 163
References: 50
Citations by year: 2026: 5 · 2025: 8 · 2024: 5 · 2023: 7 · 2022: 8 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 9 · 2015: 13 · 2014: 8 · 2013: 8 · 2012: 10
FWCI: 7.25
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
PubMed (publishedVersion)
VU Research Portal (publishedVersion, other-oa)
Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords: type 2 diabetes, endothelial dysfunction, low-grade inflammation, cardiovascular mortality, impaired glucose metabolism, cardiovascular risk, mediation analysis, endothelial function
MeSH terms: Aged, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Endothelium, Vascular, Glucose, Glucose Tolerance Test, Humans, Inflammation, Male, Middle Aged, Prospective Studies, Cohort Studies

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Endothelial Dysfunction and Low-Grade Inflammation Explain Much of the Excess Cardiovascular Mortality in Individuals With Type 2 Diabetes: The Hoorn Study

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