Effects of free fatty acids on glucose transport and IRS-1–associated phosphatidylinositol 3-kinase activity
Open accessAbstract
To examine the mechanism by which free fatty acids (FFA) induce insulin resistance in human skeletal muscle, glycogen, glucose-6-phosphate, and intracellular glucose concentrations were measured using carbon-13 and phosphorous-31 nuclear magnetic resonance spectroscopy in seven healthy subjects before and after a hyperinsulinemic-euglycemic clamp following a five-hour infusion of either lipid/heparin or glycerol/heparin. IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity was also measured in muscle biopsy samples obtained from seven additional subjects before and after an identical protocol. Rates of insulin stimulated whole-body glucose uptake. Glucose oxidation and muscle glycogen synthesis were 50%-60% lower following the lipid infusion compared with the glycerol infusion and were associated with a approximately 90% decrease in the increment in intramuscular glucose-6-phosphate concentration, implying diminished glucose transport or phosphorylation activity. To distinguish between these two possibilities, intracellular glucose concentration was measured and found to be significantly lower in the lipid infusion studies, implying that glucose transport is the rate-controlling step. Insulin stimulation, during the glycerol infusion, resulted in a fourfold increase in PI 3-kinase activity over basal that was abolished during the lipid infusion. Taken together, these data suggest that increased concentrations of plasma FFA induce insulin resistance in humans through inhibition of glucose transport activity; this may be a consequence of decreased IRS-1-associated PI 3-kinase activity.
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Intracellular accumulation of fatty acid-derived metabolites, such as fatty acyl CoA's, leads to activation of protein kinase Cθ, resulting in activation of a serine/threonine cascade that leads to increased serine phosphorylation of IRS-1, which interferes with IRS-1 tyrosine phosphorylation, resulting in decreased activation of phosphatidylinositol 3-kinase and decreased glucose transporter-4 in
“However, recent studies by our group have challenged this hypothesis and found evidence to suggest that intracellular accumulation of fatty acid-derived metabolites, such as fatty acyl CoA's, leads to activation of protein kinase Cθ , resulting in activation of a serine/threonine cascade that leads to increased serine phosphorylation of insulin receptor substrate-1 (IRS-1). IRS-1 in”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [17]
The Discussion proposes fatty acyl CoA accumulation, activation of a serine kinase (possibly PKCθ), IRS-1 serine phosphorylation, and reduced IRS-1-associated PI 3-kinase activity as a hypothesis. It does not establish the full proposed cascade or show that it reduces IRS-1 tyrosine phosphorylation or GLUT4; the Discussion presents GLUT4 effects as possibilities. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPrevious studies by our group and others have demonstrated a strong relationship between triglyceride content in liver and muscle and insulin resistance in these tissues.
“Previous studies by our group (9, 17-20) and others (7, 21, 22) have demonstrated a strong relationship between triglyceride content in liver and muscle and insulin resistance in these tissues.”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [17]
The Introduction and Discussion report that elevated plasma free fatty acids induce insulin resistance in human skeletal muscle. They do not report a relationship between triglyceride content in liver or muscle and insulin resistance in those tissues (searched: triglyceride content, intramuscular triglyceride, liver triglyceride). (LLM, conf=0.72)
Experimental — accuracy not yet measuredChronically elevated plasma free fatty acid levels cause insulin resistance in skeletal muscle.
“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 [63]
Both acute (4-hour) and chronic (4-day) physiological elevation of plasma free fatty acid concentration in insulin-sensitive individuals impairs insulin signalling and causes skeletal muscle insulin resistance.
“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 [63]
Rodent and human studies suggest increased serine phosphorylation of IRS-1 in insulin-resistant states.
“Rodent and human studies have suggested increased serine phosphorylation of IRS-1 in insulin resistant states [111, 171–173].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [171]
Muscle insulin resistance can be induced within 5 hours of lipid infusion in healthy individuals.
“IMCL is a strong predictor of insulin resistance in sedentary individuals (Krssak et al., 1999) and muscle insulin resistance can be induced within 5-hours of a lipid infusion in healthy individuals (Dresner et al., 1999), and a fatty acid derived-metabolite (e.g., DAG) has been suggested to be responsible for mediating reduced insulin signaling and insulin action.”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Dresner et al., 1999
Under diabetic conditions, endothelial cells often have reduced eNOS activity and diminished NO production.
“Thus, under diabetic conditions, ECs often have reduced eNOS activity and diminished NO production [259].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [259]
High plasma FFA concentration impairs insulin-stimulated glucose disposal rate and decreases intracellular glucose, which in turn reduces glucose oxidation and consequently enhances lipid oxidation.
“Additionally, high plasma FFA concentration impairs insulin-stimulated glucose disposal rate and decreases intracellular glucose, which in turn reduces glucose oxidation and consequently enhances lipid oxidation ([2](#r2), [8](#r8)).”
From Metabolic flexibility and insulin resistance (2008) · cites this paper as [8]
The commonly reported metabolic inflexibility and impaired glucose storage in insulin-resistant individuals is expected because cellular glucose uptake is decreased and cellular glucose available for oxidation and storage is low.
“The commonly reported metabolic inflexibility and impaired glucose storage in insulin-resistant individuals is expected, since cellular glucose uptake is decreased and cellular glucose available for oxidation and storage is low ([8](#r8)).”
From Metabolic flexibility and insulin resistance (2008) · cites this paper as [8]
The lipid-induced reduction in insulin-stimulated glucose transport is attributable to a defect in insulin signalling.
“Similarly, IRS1-associated PI3K activity was greatly reduced in the muscles of individuals being given lipid infusions, indicating that the lipid-induced reduction in insulin-stimulated glucose transport was attributable to a defect in insulin signalling.20”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [20]
FFAs reduce tyrosine phosphorylation of IRS-1/2 and inhibit the PI3K/Akt pathway, leading to decreased glucose transport and decreased phosphorylation of eNOS.
“FFAs reduce tyrosine phosphorylation of IRS-1/2 and inhibit the PI3K/Akt pathway, leading to decreased glucose transport and decreased phosphorylation of eNOS.”
From The Vasculature in Prediabetes (2018) · cites this paper as [75]
Increased tissue lipid load, as with obesity and/or sustained inactivity, may lead to accumulation of fatty acyl CoA, diacylglycerols, ceramides, products of incomplete oxidation, and ROS, all of which have been linked experimentally to reduced insulin signaling and action.
“Increased tissue lipid load, as with obesity, and/or sustained inactivity, may lead to the accumulation of fatty acyl coenzyme A (CoA), diacylglycerols, ceramides, products of incomplete oxidation, and ROS, all of which have been linked experimentally to reduced insulin signaling and action (96 -102).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [96]
Lipid excess has been linked experimentally to induction of insulin resistance and alterations in insulin signal transduction.
“Moreover, lipid excess has been linked experimentally to induction of insulin resistance (96) and alterations in insulin signal transduction (97-99).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [96]
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References 37 · Cited by 1,311
- Authors
- Dresner, A., Laurent, D., Marcucci, M., Griffin, M. E., Dufour, S., Cline, G. W., Slezak, L. A., Andersen, D. K., Hundal, R. S., Rothman, D. L., Petersen, K. F., & Shulman, G. I.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 1999-01-15
- Volume
- 103
- Issue
- 2
- Pages
- 253-259
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC407880
- OpenAlex
- W2120282127
- Cited by
- 1,311
- References
- 37
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 26 · 2023: 29 · 2022: 28 · 2021: 33 · 2020: 41 · 2019: 41 · 2018: 34 · 2017: 29 · 2016: 36 · 2015: 55 · 2014: 46 · 2013: 40 · 2012: 72
- FWCI
- 17.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- Bristol-Myers Squibb
- Yale University
- National Institutes of Health (P30 DK, RR-00125, DK-45735)
- U.S. Public Health Service (P30 DK45735)
- National Institute on Aging (P60 AG10469, P60AG010469)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01DK049230, R01 DK-49320, P30DK045735)
- National Center for Research Resources (M01RR000125)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- free fatty acids, insulin resistance, glucose transport, IRS-1, phosphatidylinositol 3-kinase, skeletal muscle, glucose-6-phosphate, intracellular glucose, lipid infusion, glycerol infusion, hyperinsulinemic-euglycemic clamp, glucose oxidation, muscle glycogen synthesis
- MeSH terms
- Adolescent, Adult, Fatty Acids, Nonesterified, Female, Glucose, Glycerol, Glycogen, Humans, Hyperinsulinism, Insulin, Insulin Resistance, Male, Magnetic Resonance Spectroscopy, Phosphoproteins, Glucose Clamp Technique, Muscle, Skeletal, Glucose-6-Phosphate, Phosphatidylinositol 3-Kinases, Lipid Metabolism, Insulin Receptor Substrate Proteins
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