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Dose-Response Effect of Elevated Plasma Free Fatty Acid on Insulin Signaling
Open accessAbstract
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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In the citing paper
“It is well established that chronically elevated plasma FFA levels cause insulin resistance in skeletal muscle [1, 12, 14, 62–65].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [65]
Experimental — accuracy not yet measuredIn the citing paper
“Both acute (4 hours) and chronic (4 days) physiologic elevation of plasma FFA concentration in insulin sensitive individuals impairs insulin signaling and causes insulin resistance in skeletal muscle [28, 62–68].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [65]
In the citing paper
“The inhibition of insulin signaling and induction of skeletal muscle insulin resistance caused by elevation in the plasma FFA concentration is dose dependent [65].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [65]
In the citing paper
“Such observations are most likely attributed to testosterone-induced changes in lipid metabolism and/or altered postreceptor insulin signaling in muscle (54) and also improved insulin sensitivity enhancing muscle lipid uptake (55).”
From Onset of effects of testosterone treatment and time span until maximum effects are achieved (2011) · cites this paper as [54]
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PROTEIN MEASUREMENT WITH THE FOLIN PHENOL REAGENT
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DeFronzo, R. A. (2009) · Diabetes · doi:10.2337/db09-9028 · Cited by 3,016
Self-citationPathogenesis of type 2 diabetes mellitus
DeFronzo, R. A. (2004) · Medical Clinics of North America · doi:10.1016/j.mcna.2004.04.013 · Cited by 1,342
Self-citationAkt signalling in health and disease
Hers, I., Vincent, E. E., & Tavaré, J. M. (2011) · Cellular Signalling · doi:10.1016/j.cellsig.2011.05.004 · Cited by 1,268
Disordered lipid metabolism and the pathogenesis of insulin resistance.
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Cusi, K., Orsak, B., Bril, F., Lomonaco, R., Hecht, J., Ortiz-Lopez, C., Tio, F., Hardies, J., Darland, C., Musi, N., et al. (2016) · Annals of Internal Medicine · doi:10.7326/m15-1774 · Cited by 1,024
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Metadata
- 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)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-06-01
- Volume
- 54
- Issue
- 6
- Pages
- 1640-1648
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- 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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