Cited by 1,652Nitric Oxide and Endothelin EffectsDiabetes, Cardiovascular Risks, and LipoproteinsCardiovascular Health and Disease Prevention

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Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms

Kim, Jeong-a, Montagnani, Monica, Koh, Kwang Kon, Quon, Michael J.·2006·Circulation

DOI 10.1161/circulationaha.105.563213

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Abstract

Endothelial dysfunction contributes to cardiovascular diseases, including hypertension, atherosclerosis, and coronary artery disease, which are also characterized by insulin resistance. Insulin resistance is a hallmark of metabolic disorders, including type 2 diabetes mellitus and obesity, which are also characterized by endothelial dysfunction. Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium to stimulate production of the vasodilator nitric oxide (NO). Indeed, NO-dependent increases in blood flow to skeletal muscle account for 25% to 40% of the increase in glucose uptake in response to insulin stimulation. Phosphatidylinositol 3-kinase-dependent insulin-signaling pathways in endothelium related to production of NO share striking similarities with metabolic pathways in skeletal muscle that promote glucose uptake. Other distinct nonmetabolic branches of insulin-signaling pathways regulate secretion of the vasoconstrictor endothelin-1 in endothelium. Metabolic insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase-dependent signaling, which in endothelium may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased blood flow, which worsens insulin resistance. Therapeutic interventions in animal models and human studies have demonstrated that improving endothelial function ameliorates insulin resistance, whereas improving insulin sensitivity ameliorates endothelial dysfunction. Taken together, cellular, physiological, clinical, and epidemiological studies strongly support a reciprocal relationship between endothelial dysfunction and insulin resistance that helps to link cardiovascular and metabolic diseases. In the present review, we discuss pathophysiological mechanisms, including inflammatory processes, that couple endothelial dysfunction with insulin resistance and emphasize important therapeutic implications.

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Authors: Kim, J.-A., Montagnani, M., Koh, K. K., & Quon, M. J.
Affiliations: National Institutes of Health (US)
ORCID: Kim, Jeong-a
Montagnani, Monica
Koh, Kwang Kon
Quon, Michael J.
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2006-04-18
Volume: 113
Issue: 15
Pages: 1888-1904
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/circulationaha.105.563213
OpenAlex: W2126412451
Cited by: 1,652
References: 186
Citations by year: 2026: 68 · 2025: 80 · 2024: 61 · 2023: 55 · 2022: 67 · 2021: 71 · 2020: 67 · 2019: 64 · 2018: 76 · 2017: 70 · 2016: 76 · 2015: 99 · 2014: 96 · 2013: 119 · 2012: 108
FWCI: 61.64
Type: journal article
Language: en
Open access: closed
Locations: Circulation (publishedVersion)
PubMed (publishedVersion)
CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
Funders: American Diabetes Association
National Institutes of Health
National Center for Complementary and Alternative Medicine
Topics: Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
Keywords: insulin resistance, endothelial dysfunction, nitric oxide, endothelin-1, phosphatidylinositol 3-kinase signaling, glucose uptake, skeletal muscle blood flow, type 2 diabetes, obesity, cardiovascular disease, inflammation, bidirectional relationship
MeSH terms: Animals, Disease Models, Animal, Endothelium, Vascular, Glucose, Hemodynamics, Homeostasis, Humans, Insulin, Insulin Resistance, Signal Transduction, Metabolic Syndrome

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Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms

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