Cited by 404Diabetes, Cardiovascular Risks, and LipoproteinsDiet, Metabolism, and DiseaseMetabolism, Diabetes, and Cancer

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Dose-Response Effect of Elevated Plasma Free Fatty Acid on Insulin Signaling

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Belfort, Renata, Mandarino, Lawrence, Kashyap, Sangeeta, Wirfel, Kelly, Pratipanawatr, Thongchai, Berria, Rachele, DeFronzo, Ralph A., Cusi, Kenneth·2005·Diabetes

DOI 10.2337/diabetes.54.6.1640

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Abstract

The dose-response relationship between elevated plasma free fatty acid (FFA) levels and impaired insulin-mediated glucose disposal and insulin signaling was examined in 21 lean, healthy, normal glucose-tolerant subjects. Following a 4-h saline or Liposyn infusion at 30 (n = 9), 60 (n = 6), and 90 (n = 6) ml/h, subjects received a 2-h euglycemic insulin (40 mU · m−2 · min−1) clamp. Basal plasma FFA concentration (∼440 μmol/l) was increased to 695, 1,251, and 1,688 μmol/l after 4 h of Liposyn infusion and resulted in a dose-dependent reduction in insulin-stimulated glucose disposal (Rd) by 22, 30, and 34%, respectively (all P < 0.05 vs. saline control). At the lowest lipid infusion rate (30 ml/h), insulin receptor and insulin receptor substrate (IRS)-1 tyrosine phosphorylation, phosphatidylinositol (PI) 3-kinase activity associated with IRS-1, and Akt serine phosphorylation were all significantly impaired (P < 0.05–0.01). The highest lipid infusion rate (90 ml/h) caused a further significant reduction in all insulin signaling events compared with the low-dose lipid infusion (P < 0.05–0.01) whereas the 60-ml/h lipid infusion caused an intermediate reduction in insulin signaling. However, about two-thirds of the maximal inhibition of insulin-stimulated glucose disposal already occurred at the rather modest increase in plasma FFA induced by the low-dose (30-ml/h) lipid infusion. Insulin-stimulated glucose disposal was inversely correlated with both the plasma FFA concentration after 4 h of lipid infusion (r = −0.50, P = 0.001) and the plasma FFA level during the last 30 min of the insulin clamp (r = −0.54, P < 0.001). PI 3-kinase activity associated with IRS-1 correlated with insulin-stimulated glucose disposal (r = 0.45, P < 0.01) and inversely with both the plasma FFA concentration after 4 h of lipid infusion (r = −0.39, P = 0.01) and during the last 30 min of the insulin clamp (r = −0.43, P < 0.01). In summary, in skeletal muscle of lean, healthy subjects, a progressive increase in plasma FFA causes a dose-dependent inhibition of insulin-stimulated glucose disposal and insulin signaling. The inhibitory effect of plasma FFA was already significant following a rather modest increase in plasma FFA and develops at concentrations that are well within the physiological range (i.e., at plasma FFA levels observed in obesity and type 2 diabetes).

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Authors: Belfort, R., Mandarino, L., Kashyap, S., Wirfel, K., Pratipanawatr, T., Berria, R., DeFronzo, R. A., & Cusi, K.
Affiliations: The University of Texas at San Antonio Health Science Center (US)
ORCID: Mandarino, Lawrence
Kashyap, Sangeeta
Pratipanawatr, Thongchai
DeFronzo, Ralph A.
Cusi, Kenneth
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2005-06-01
Volume: 54
Issue: 6
Pages: 1640-1648
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diabetes.54.6.1640
OpenAlex: W2115433418
Cited by: 404
References: 74
Citations by year: 2026: 9 · 2025: 10 · 2024: 22 · 2023: 10 · 2022: 18 · 2021: 21 · 2020: 24 · 2019: 15 · 2018: 14 · 2017: 20 · 2016: 15 · 2015: 23 · 2014: 28 · 2013: 26 · 2012: 15
FWCI: 11.03
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Diabetes (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-24092, F32DK061189, R01DK024092)
National Center for Research Resources (M01RR01346, M01RR001346)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: plasma free fatty acids, insulin signaling, insulin resistance, insulin-stimulated glucose disposal, dose-response relationship, insulin receptor tyrosine phosphorylation, IRS-1, phosphatidylinositol 3-kinase, hyperinsulinemic-euglycemic clamp
MeSH terms: Adult, Dose-Response Relationship, Drug, Emulsions, Fat Emulsions, Intravenous, Fatty Acids, Nonesterified, Female, Glucose, Humans, Insulin, Male, Safflower Oil, Soybean Oil, Signal Transduction, Muscle, Skeletal, Lecithins

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Dose-Response Effect of Elevated Plasma Free Fatty Acid on Insulin Signaling

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