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Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation
Open accessAbstract
We have recently shown that insulin-resistant obese subjects exhibit impaired endothelial function. Here, we test the hypothesis that elevation of circulating FFA to levels seen in insulin-resistant subjects can impair endothelial function. We studied leg blood flow responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (Mch) or the endothelium-independent vasodilator sodium nitroprusside during the infusion of saline and after raising systemic circulating FFA levels exogenously via a low- or high-dose infusion of Intralipid plus heparin or endogenously by an infusion of somatostatin (SRIF) to produce insulinopenia in groups of lean healthy humans. After 2 h of infusion of Intralipid plus heparin, FFA levels increased from 562+/-95 to 1,303+/-188 micromol, and from 350+/-35 to 3,850+/-371 micromol (P < 0.001) vs. saline for both low- and high-dose groups, respectively. Mch-induced vasodilation relative to baseline was reduced by approximately 20% in response to the raised FFA levels in both groups (P < 0.05, saline vs. FFA, ANOVA). In contrast, similar FFA elevation did not change leg blood flow responses to sodium nitroprusside. During the 2-h SRIF infusion, insulin levels fell, and FFA levels rose from 474+/-22 to 1,042+/-116 micromol (P < 0.01); Mch-induced vasodilation was reduced by approximately 20% (P < 0.02, saline vs. SRIF, ANOVA). Replacement of basal insulin levels during SRIF resulted in a fall of FFA levels from 545+/-47 to 228+/-61 micromol, and prevented the impairment of Mch-induced vasodilation seen with SRIF alone. In conclusion, (a) elevated circulating FFA levels cause endothelial dysfunction, and (b) impaired endothelial function in insulin-resistant humans may be secondary to the elevated FFA concentrations observed in these patients.
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“The experimental induction of IR in rats (31) and in humans (7) resulted in reductions in blood flow responses.”
From Improved Endothelial Function With Metformin in Type 2 Diabetes Mellitus (2001) · cites this paper as [7]
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Metadata
- Authors
- Steinberg, H. O., Tarshoby, M., Monestel, R., Hook, G., Cronin, J., Johnson, A., Bayazeed, B., & Baron, A. D.
- Affiliations
- Indiana University (US)
- Indiana University – Purdue University Indianapolis (US)
- ORCID
- Tarshoby, M
- Venue
- Journal of Clinical Investigation
- Published
- 1997-09-01
- Volume
- 100
- Issue
- 5
- Pages
- 1230-1239
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508300
- OpenAlex
- W2086785365
- Cited by
- 761
- References
- 16
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 17 · 2023: 20 · 2022: 9 · 2021: 19 · 2020: 29 · 2019: 11 · 2018: 19 · 2017: 20 · 2016: 12 · 2015: 22 · 2014: 17 · 2013: 28 · 2012: 33
- FWCI
- 10.61
- 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 (DK 20452, DK42469)
- National Center for Research Resources (MO1-RR75019)
- 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 Function and Risk Factors
- Keywords
- free fatty acids, endothelial dysfunction, endothelium-dependent vasodilation, insulin resistance, methacholine, sodium nitroprusside, leg blood flow, somatostatin, insulin deficiency, Intralipid, obesity, insulin replacement therapy
- MeSH terms
- Adult, Blood Pressure, Endothelium, Vascular, Fat Emulsions, Intravenous, Fatty Acids, Nonesterified, Female, Humans, Insulin, Leg, Male, Nitroprusside, Somatostatin, Vasodilation, Methacholine Chloride
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