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Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological Mechanisms
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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“Endothelial dysfunction is attributed to many causes, including oxidative stress, chronic inflammation, and endothelium activation, in diabetes, which exhibits excessive free fatty acid (FFA), insulin resistance, and/or hyperglycemia [216,217].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [217]
In the citing paper
“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 [50]
In the citing paper
“insulin resistance is always associated with impaired NO availability, suggesting that a reciprocal relationship exists between insulin activation and endothelial function [50,53].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [50]
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Metadata
- Authors
- Kim, J.-A., Montagnani, M., Koh, K. K., & Quon, M. J.
- Affiliations
- National Institutes of Health (US)
- Venue
- Circulation
- Published
- 2006-04-18
- Volume
- 113
- Issue
- 15
- Pages
- 1888-1904
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- 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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