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Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance
Open accessAbstract
To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulin-mediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by - 50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable increments in LBF in all groups. Regression analysis revealed a significant inverse correlation between the maximal LBF change in response to MCh and body fat content. Thus, obesity/insulin resistance is associated with (a) blunted endothelium-dependent, but normal endothelium-independent vasodilation and (b) failure of euglycemic hyperinsulinemia to augment endothelium-dependent vasodilation. Therefore, obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation. This endothelial dysfunction could contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects.
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“Furthermore, IR per se has a direct impact on endothelial function, distinct from effects related to unfavorable changes in lipid composition or blood pressure (9).”
From Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus (2001) · cites this paper as [9]
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“40 However, numerous studies have shown that this action of insulin is severely impaired in subjects with various components of the metabolic syndrom”
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Wyne, K. L. (2003) · The American Journal of Medicine · doi:10.1016/j.amjmed.2003.09.004 · Cited by 90
Coronary Circulatory Function in Patients with the Metabolic Syndrome
Carli, M. F. D., Charytan, D. M., McMahon, G. T., Ganz, P., Dorbala, S., & Schelbert, H. R. (2011) · Journal of Nuclear Medicine · doi:10.2967/jnumed.110.082883 · Cited by 90
“reported a blunted increase in leg blood flow in response to methacholine in a small group of young obese and insulin-resistant subjects, compared with a group of lean controls (35).”
ResultInsulin resistance is associated with subclinical vascular disease in humans
Adeva‐Andany, M. M., Ameneiros-Rodríguez, E., Fernández‐Fernández, C., Domínguez-Montero, A., & Funcasta-Calderón, R. (2019) · World Journal of Diabetes · doi:10.4239/wjd.v10.i2.63 · Cited by 91
Tarkun, İ., Çetinarslan, B., Türemen, E., Şahı̇n, T., Cantürk, Z., & Komşuoğlu, B. (2005) · European Journal of Endocrinology · doi:10.1530/eje.1.01948 · Cited by 89
“Studies showing a link between endothelial dysfunction and insulin resistance have been reported (13, 14 ).”
BackgroundEndothelium-specific activation of NAD(P)H oxidase in aortas of exogenously hyperinsulinemic rats
Kashiwagi, A., Shinozaki, K., Nishio, Y., Maegawa, H., Maeno, Y., Kanazawa, A., Kojima, H., Haneda, M., Hidaka, H., Yasuda, H., et al. (1999) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1999.277.6.e976 · Cited by 89
Walter, L. C., Lindquist, K. J., & Covinsky, K. E. (2004) · Annals of Internal Medicine · doi:10.7326/0003-4819-140-9-200405040-00007 · Cited by 87
Pontiroli, A. E., Pizzocri, P., Koprivec, D., Vedani, P., Marchi, M. D., Arcelloni, C., Paroni, R. C., Esposito, K., & Giugliano, D. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1500195 · Cited by 88
“In addition, both hyperglycaemia and insulin administration increase circulating levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide (4, 5). However, the majority of patients with T2DM are obese, and this raises the question of the importance of diabetes per se and of obesity per se .I n fact, endothelium-…”
BackgroundMuris, D. M. J., Houben, A. J. H. M., Schram, M. T., & Stehouwer, C. D. A. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-012-9231-7 · Cited by 86
“We [6–8] and others [9, 10, 62, 101, 102] have demonstrated that microvascular dysfunction is impaired in obesity and that microvascular dysfunction develops progressively along with an increase in adipose tissue [40, 67, 103].”
Insulin resistance and endothelial cell dysfunction: studies in mammalian models
Kearney, M. T., Duncan, E. R., Kahn, M., & Wheatcroft, S. B. (2007) · Experimental Physiology · doi:10.1113/expphysiol.2007.039172 · Cited by 89
“Seminal studies from the laboratories of Alain Baron (Steinberg et al. 1996) and Michael Quon (Zeng & Quon, 1996; Zeng et al.”
BackgroundInfluentialInsulin resistance and endothelial dysfunction in smokers: effects of vitamin C
Hirai, N., Kawano, H., Hirashima, O., Motoyama, T., Moriyama, Y., Sakamoto, T., Kugiyama, K., Ogawa, H., Nakao, K., & Yasue, H. (2000) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2000.279.3.h1172 · Cited by 87
“The impairment of the insulin-induced increase in skeletal muscle blood flow has been reported in the insulin-resistant state (33, 41).”
BackgroundElectronic Cigarette Use and the Risk of Cardiovascular Diseases
Espinoza-Derout, J., Shao, X. M., Lao, C. J., Hasan, K. M., Rivera, J. C., Jordan, M. C., Echeverria, V., Roos, K. P., Sinha-Hikim, A. P., & Friedman, T. C. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.879726 · Cited by 103
“smokers have been reproduced (65–71) and support other studies showing that insulin resistance can lead to both dyslipidemia (72) and endothelial dysfunction (73) seen in smokers.”
ResultChan, N. N., Colhoun, H. M., & Vallance, P. J. (2001) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(01)01669-2 · Cited by 86
“Our data are consistent with previous studies showing that higher BMI is associated with reduced endothelium-dependent (BK and ACh responses) vasodilation (3,21).”
BackgroundResultAli, M. I., Ketsawatsomkron, P., de Chantemèle, E. J. B., MINTZ, J. D., Muta, K., Salet, C., Black, S. M., Tremblay, M. L., Fulton, D. J., Marrero, M. B., et al. (2009) · Circulation Research · doi:10.1161/circresaha.109.206318 · Cited by 85
Kim, G.-J., Song, D. H., Yoo, H. S., Chung, K., Lee, K. J., & An, J. H. (2017) · Nutrients · doi:10.3390/nu9010041 · Cited by 85
Baron, A. (1999) · The American Journal of Cardiology · doi:10.1016/s0002-9149(99)00354-9 · Cited by 85
Kernan, W. N., Inzucchi, S. E., Viscoli, C. M., Brass, L. M., Bravata, D. M., Shulman, G. I., McVeety, J. C., & Horwitz, R. I. (2003) · Stroke · doi:10.1161/01.str.0000071108.00234.0e · Cited by 84
Energy Drinks and Their Impact on the Cardiovascular System: Potential Mechanisms
Grasser, E. K., Miles-Chan, J. L., Charrière, N., Loonam, C., Dulloo, A. G., & Montani, J. (2016) · Advances in Nutrition · doi:10.3945/an.116.012526 · Cited by 87
“(72) observed that endothelial function is impaired in human obesity and type 2 diabetes, both of which are conditions associated with insulin resistance.”
BackgroundBougoulia, M., Triantos, A., & Koliakos, G. (2006) · HORMONES · doi:10.14310/horm.2002.11190 · Cited by 85
Bourgoin, F., Bachelard, H., Badeau, M., Mélançon, S., Pǐtre, M., Larivière, R., & Nadeau, A. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00516.2008 · Cited by 84
FFA-Induced Endothelial Dysfunction Can Be Corrected by Vitamin C
Pleiner, J., Schaller, G., Mittermayer, F., Bayerle‐Eder, M., Roden, M., & Wolzt, M. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.6.8596 · Cited by 87
Higashi, Y., Sasaki, S., Nakagawa, K., Kimura, M., Noma, K., Sasaki, S., Hara, K., Matsuura, H., Goto, C., Oshima, T., et al. (2003) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(03)00630-2 · Cited by 84
“Several investigators, including ourselves, have shown that endotheliumdependent vasodilation of forearm and leg circulation is impaired in obese individuals compared with lean individuals (6,7).”
BackgroundResultMicrovascular Endothelial Dysfunction in Human Obesity: Role of TNF-α
Virdis, A., Colucci, R., Bernardini, N., Blandizzi, C., Taddei, S., & Masi, S. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00512 · Cited by 89
“The first demonstration that obesity per se can cause endothelial dysfunction was reported by Steinberg et al (11), who documented reduced endothelium-dependent vasodilation to methacholine in the leg microcirculation of obese patients.”
BackgroundSandu, O. A., Ragolia, L., & Begum, N. (2000) · Diabetes · doi:10.2337/diabetes.49.12.2178 · Cited by 84
Obesity as a premature aging phenotype — implications for sarcopenic obesity
Nunan, E. L., Wright, C. L., Semola, O. A., Subramanian, M., Balasubramanian, P., Lovern, P. C., Fancher, I. S., & Butcher, J. T. (2022) · GeroScience · doi:10.1007/s11357-022-00567-7 · Cited by 83
Ballard, K. D., Bruno, R. S., Seip, R. L., Quann, E. E., Volk, B. M., Freidenreich, D. J., Kawiecki, D. M., Kupchak, B. R., Chung, M., Kraemer, W. J., et al. (2009) · Nutrition Journal · doi:10.1186/1475-2891-8-34 · Cited by 83
“Impaired NO· signaling and endothelial dysfunction have been implicated in metabolic syndrome [2] and cardiovascular disease [3].”
Central Obesity Is an Independent Risk Factor for Albuminuria in Nondiabetic South Asian Subjects
Shaw, P. K. C., Berger, S. P., Mallat, M. J. K., Frölich, M., Dekker, F. W., & Rabelink, T. J. (2007) · Diabetes Care · doi:10.2337/dc07-0028 · Cited by 85
Dessein, P. H., Joffe, B. I., Stanwix, A. E., Botha, A. S., & Moomal, Z. (2002) · PubMed · Cited by 83
Glucose transport in brain and retina: implications in the management and complications of diabetes
Kumagai, A. K. (1999) · Diabetes/Metabolism Research and Reviews · doi:10.1002/(sici)1520-7560(199907/08)15:4 · Cited by 159
Mechanisms of endothelial dysfunction in obesity-associated hypertension
Lobato, N. S., Filgueira, F. P., Akamine, E. H., Tostes, R. C., de Carvalho, M. H. C., & Fortes, Z. B. (2012) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x2012007500058 · Cited by 84
“Given that activation of endothelial adrenergic receptors releases endothelium-derived relaxant factors like NO and endothelium-derived contracting factors such as ET-1 (57,58), disturbances in the balanced release of these factors as a consequence of altered activity of the sympathetic nervous system may explain the…”
BackgroundVascular nitric oxide resistance in type 2 diabetes
Bahadoran, Z., Mirmiran, P., Kashfi, K., & Ghasemi, A. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05935-5 · Cited by 100
“ET-independent, NO•-dependent relaxation has been reported to be decreased in some prediabetes subjects by 2633% [23, 30], but it preserves in others [28, 29].”
BackgroundMethodInfluentialNitric oxide dysfunction in vascular endothelium and platelets: role in essential hypertension
Gkaliagkousi, Ε., Δούμα, Σ., Zamboulis, C., & Ferro, A. (2009) · Journal of Hypertension · doi:10.1097/hjh.0b013e328330e89a · Cited by 81
Ohtoshi, K., Kaneto, H., Node, K., Nakamura, Y., Shiraiwa, T., Matsuhisa, M., & Yamasaki, Y. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.03.171 · Cited by 82
Caballero, A. E. (2005) · Archives of Medical Research · doi:10.1016/j.arcmed.2005.03.013 · Cited by 82
Bigornia, S., Mott, M. M., Hess, D. T., Apovian, C. M., McDonnell, M. E., Duess, M., Kluge, M. A., Fiscale, A. J., Vita, J. A., & Gokce, N. (2010) · Obesity · doi:10.1038/oby.2009.482 · Cited by 80
“Abnormalities in endothelial function worsen with increased weight burden owing to several mechanisms associated with excess fat mass including impaired glucose tolerance, insulin resistance, metabolic dysregulation, adipocytokine release, and systemic inflammation that play a key role in the evolution and clinical ex…”
Background
Metadata
- Authors
- Steinberg, H. O., Chaker, H., Leaming, R., Johnson, A., Brechtel, G., & Baron, A. D.
- Affiliations
- Indiana University (US)
- Richard L. Roudebush VA Medical Center (US)
- Indiana University Hospital (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1996-06-01
- Volume
- 97
- Issue
- 11
- Pages
- 2601-2610
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC507347
- OpenAlex
- W1982811953
- Cited by
- 1,687
- References
- 59
- Citations by year
- 2026: 11 · 2025: 23 · 2024: 17 · 2023: 30 · 2022: 19 · 2021: 32 · 2020: 30 · 2019: 36 · 2018: 36 · 2017: 46 · 2016: 50 · 2015: 51 · 2014: 69 · 2013: 69 · 2012: 61
- FWCI
- 18.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- American Heart Association
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK42469, P60DK020542, DK20542)
- National Center for Research Resources (M 01-RR750-19)
- 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
- obesity, insulin resistance, endothelial dysfunction, endothelium-dependent vasodilation, euglycemic hyperinsulinemia, leg blood flow, methacholine, sodium nitroprusside, type 2 diabetes, fat mass, atherosclerosis risk
- MeSH terms
- Adult, Blood Glucose, Blood Pressure, Cholesterol, Diabetes Mellitus, Type 2, Endothelium, Vascular, Fatty Acids, Nonesterified, Glucose, Humans, Hyperinsulinism, Infusions, Intra-Arterial, Infusions, Intravenous, Insulin, Insulin Resistance, Leg, Cholesterol, HDL, Cholesterol, LDL, Nitroprusside, Obesity, Reference Values, Regional Blood Flow, Syndrome, Time Factors, Triglycerides, Vasodilation, Glucose Clamp Technique, Body Mass Index, Methacholine Chloride
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