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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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Lozano, I. I., der Werf, R. V., Bietiger, W., Seyfritz, E., Péronet, C., Pinget, M., Jeandidier, N., Maillard, É., Marchioni, E., Sigrist, S., et al. (2016) · Nutrition & Metabolism · doi:10.1186/s12986-016-0074-1 · Cited by 349
“In addition, a number of disorders may induce endothelial dysfunction, such as obesity, visceral fat distribution [57], impaired fasting glucose, hyperglycaemia [58], insulin resistance [59], oxidative stress [60], and inflammation [61] all of which were observed in our models, and reported in other studies [62].”
ResultInsulin Causes Endothelial Dysfunction in Humans: Sites and Mechanisms
Arcaro, G., Cretti, A., Balzano, S., Lechi, A., Muggeo, M., Bonora, E., & Bonadonna, R. C. (2002) · Circulation · doi:10.1161/hc0502.103333 · Cited by 407
Roberts, C. K., Barnard, R. J., Sindhu, R. K., Jurczak, M., Ehdaie, A., & Vaziri, N. D. (2006) · Metabolism · doi:10.1016/j.metabol.2006.02.022 · Cited by 322
“Metabolic syndrome, otherwise known as syndrome X or insulin resistance syndrome, is defined by the presence of insulin resistance, hyperinsulinemia, and some combination of obesity, dyslipidemia, inflammation, endothelial dysfunction, and hypertension [1-9].”
BackgroundInsulin Resistance and Atherosclerosis
Nigro, J., Osman, N., Dart, A. M., & Little, P. J. (2006) · Endocrine Reviews · doi:10.1210/er.2005-0007 · Cited by 321
“In insulin resistance, VSMCs have an impaired responsiveness to NO, resulting in increased contraction that can result in an imbalance in vascular tone and may impact on insulin-mediated delivery of glucose to muscle in the insulin-resistant state (96).”
BackgroundPotenza, M. A., Marasciulo, F. L., Chieppa, D. M., Brigiani, G. S., Formoso, G., Quon, M. J., & Montagnani, M. (2005) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00092.2005 · Cited by 314
“greater nutritive blood flow to skeletal muscle (53).”
BackgroundGonzález-Gay, M. Á., Matias, J. M. D., González‐Juanatey, C., Garcı́a-Porrúa, C., Sanchez-Andrade, A., Martin, J. J., & Llorca, J. (2006) · PubMed · Cited by 313
Woo, K. S., Chook, P., Yu, C. C.-W., Sung, R. Y. T., Qiao, M., Leung, S. S. F., Lam, C. W. K., Metreweli, C., & Celermajer, D. S. (2004) · International Journal of Obesity · doi:10.1038/sj.ijo.0802539 · Cited by 316
Obesity, Insulin Resistance, and the Metabolic Syndrome
Lteif, A. A., Han, K., & Mather, K. J. (2005) · Circulation · doi:10.1161/circulationaha.104.520130 · Cited by 308
Pathophysiological implications of insulin resistance on vascular endothelial function
Wheatcroft, S. B., Williams, I. L., Shah, A. M., & Kearney, M. T. (2003) · Diabetic Medicine · doi:10.1046/j.1464-5491.2003.00869.x · Cited by 316
Leptin and hyperleptinemia - from friend to foe for cardiovascular function
Ren, J. (2004) · Journal of Endocrinology · doi:10.1677/joe.0.1810001 · Cited by 305
“…activation of the sympathetic autonomic nervous system and impairment of endothelial function are the two pivotal phenotypical traits in obesity (Steinberg et al. 1996, Julius et al. 2000, Kuo et al. 2003), the cellular mechanisms responsible for sympathetic hyperactivity and endothelial…”
BackgroundRask‐Madsen, C., Li, Q., Freund, B., Feather, D., Abramov, R., Wu, I., Chen, K., Hiraoka‐Yamamoto, J., Goldenbogen, J., Sotiropoulos, K. B., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.03.013 · Cited by 313
“, 1999) and blunted vascular effects of insulin (Steinberg et al., 1996).”
BackgroundResultInfluentialObesity Blunts Insulin-Mediated Microvascular Recruitment in Human Forearm Muscle
Clerk, L. H., Keske, M. A., Jahn, L. A., Liu, Z., Lindner, J. R., & Barrett, E. J. (2006) · Diabetes · doi:10.2337/db05-1373 · Cited by 305
“Additionally, evidence from several (but not all [5]) studies indicates that obesity is associated with impaired endothelial function, as assessed by measurements of either responsiveness of resistance arterioles to infusion of cholinergic vasodilators (6) or flow-mediated conduit vessel relaxation (7).”
BackgroundMori, T. A., Bao, D. Q., Burke, V., Puddey, I. B., Watts, G. F., & Beilin, L. J. (1999) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/70.5.817 · Cited by 294
Tarkun, İ., ARSLAN, B., Cantürk, Z., Türemen, E., Şahı̇n, T., & Duman, C. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0751 · Cited by 298
Adolescent Obesity: Diet Quality, Psychosocial Health, and Cardiometabolic Risk Factors
Ruiz, L. D., Zuelch, M. L., Dimitratos, S. M., & Scherr, R. E. (2019) · Nutrients · doi:10.3390/nu12010043 · Cited by 336
Prevention of Type 2 Diabetes Mellitus Through Inhibition of the Renin-Angiotensin System
Scheen, A. J. (2004) · Drugs · doi:10.2165/00003495-200464220-00004 · Cited by 293
Human C-reactive protein and the metabolic syndrome
Devaraj, S., Singh, U. S., & Jialal, I. (2009) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32832ac03e · Cited by 295
Vascular dysfunction in diabetes mellitus
Feener, E. P., & King, G. L. (1997) · The Lancet · doi:10.1016/s0140-6736(97)90022-2 · Cited by 287
Obesity and hypertension: two epidemics or one?
Davy, K. P., & Hall, J. E. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00707.2003 · Cited by 280
“There is increasing evidence that obesity in humans is associated with peripheral (146) and coronary (6) endothelial dysfunction.”
BackgroundJonk, A. M., Houben, A. J. H. M., de Jongh, R. T., Serné, E. H., Schaper, N. C., & Stehouwer, C. D. A. (2007) · Physiology · doi:10.1152/physiol.00012.2007 · Cited by 286
“Obese subjects showed blunted vasodilation in response to classic endothelium-dependent vasodilators in skin and resistance arteries (24, 29, 101).”
BackgroundEndothelial inflammation in insulin resistance
SJOHOLM, A., & NYSTROM, T. (2005) · The Lancet · doi:10.1016/s0140-6736(05)70804-7 · Cited by 278
Role of endothelial dysfunction in insulin resistance
Hsueh, W. A., & Quiñones, M. J. (2003) · The American Journal of Cardiology · doi:10.1016/s0002-9149(03)00611-8 · Cited by 271
Prior, J. O., Quiñones, M. J., Hernandez‐Pampaloni, M., Facta, A. D., Schindler, T. H., Sayre, J. W., Hsueh, W. A., & Schelbert, H. R. (2005) · Circulation · doi:10.1161/01.cir.0000164232.62768.51 · Cited by 275
Insulin Resistance, Hyperinsulinemia, and Renal Injury: Mechanisms and Implications
Sarafidis, P. A., & Ruilope, L. M. (2006) · American Journal of Nephrology · doi:10.1159/000093632 · Cited by 273
“in a dose-dependent manner. In contrast, several other studies have documented that in insulin-resistant states, such as obesity [”
ResultRegulation of obesity and insulin resistance by nitric oxide
Sansbury, B. E., & Hill, B. G. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.05.016 · Cited by 274
“The fact that obesity in humans is associated with decreased blood flow in response to methacholine [230], bradykinin [231,232], substance P and acetylcholine [232], shear stress [233], and insulin [234,235] seems to suggest that the”
BackgroundType II Diabetes Abrogates Sex Differences in Endothelial Function in Premenopausal Women
Steinberg, H. O., Paradisi, G., Cronin, J., Crowde, K., Hempfling, A., Brechtel, G., & Baron, A. (2000) · Circulation · doi:10.1161/01.cir.101.17.2040 · Cited by 271
Antioxidants, diabetes and endothelial dysfunction
Laight, D. W. (2000) · Cardiovascular Research · doi:10.1016/s0008-6363(00)00054-7 · Cited by 264
Gilchrist, M., Winyard, P. G., Aizawa, K., Anning, C., Shore, A., & Benjamin, N. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.01.024 · Cited by 261
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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