Mechanism by Which Fatty Acids Inhibit Insulin Activation of Insulin Receptor Substrate-1 (IRS-1)-associated Phosphatidylinositol 3-Kinase Activity in Muscle
Open accessAbstract
Recent studies have demonstrated that fatty acids induce insulin resistance in skeletal muscle by blocking insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-kinase). To examine the mechanism by which fatty acids mediate this effect, rats were infused with either a lipid emulsion (consisting mostly of 18:2 fatty acids) or glycerol. Intracellular C18:2 CoA increased in a time-dependent fashion, reaching an approximately 6-fold elevation by 5 h, whereas there was no change in the concentration of any other fatty acyl-CoAs. Diacylglycerol (DAG) also increased transiently after 3-4 h of lipid infusion. In contrast there was no increase in intracellular ceramide or triglyceride concentrations during the lipid infusion. Increases in intracellular C18:2 CoA and DAG concentration were associated with protein kinase C (PKC)-theta activation and a reduction in both insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1 associated PI3-kinase activity, which were associated with an increase in IRS-1 Ser(307) phosphorylation. These data support the hypothesis that an increase in plasma fatty acid concentration results in an increase in intracellular fatty acyl-CoA and DAG concentrations, which results in activation of PKC-theta leading to increased IRS-1 Ser(307) phosphorylation. This in turn leads to decreased IRS-1 tyrosine phosphorylation and decreased activation of IRS-1-associated PI3-kinase activity resulting in decreased insulin-stimulated glucose transport activity.
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Lipid accumulation in skeletal muscle occurs with insulin resistance.
“Lipid accumulation in skeletal muscle (7) or metabolic overload in mitochondria (8) have also been shown to occur with IR”
From TFAM Enhances Fat Oxidation and Attenuates High-Fat Diet–Induced Insulin Resistance in Skeletal Muscle (2019) · cites this paper as [7]
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 [64]
Chronically 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 [64]
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 [173]
GLUT4 is the insulin-regulatable glucose transporter in skeletal muscle, has a Km of about 5 mmol/L close to plasma glucose, and is associated with HK-II.
“GLUT4, the insulin regulatable transporter, is found in skeletal muscle, has a Km of approximately 5 mmol/L, which is close to that of the plasma glucose concentration, and is associated with HK-II [173, 174].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [173]
Increased levels of fatty acyl-CoA in general are associated with insulin resistance, and C18:2-CoA accumulation is a potential indicator of insulin resistance.
“While increased levels of fatty acyl-CoA in general are associated with IR and in C18:2-CoA accumulation is a potential indicator of IR [115,117].”
From Omega-3 Fatty Acids and Skeletal Muscle Health (2015) · cites this paper as [117]
An overabundance of saturated fatty acids such as palmitate can induce insulin resistance through the accumulation of lipid derivatives including DAGs, ceramides and long chain acyl-CoAs in the cytosol, which in turn can interfere with IRS1-PKB signalling.
“In particular, an overabundance of SFA (e.g., Palmitate) can induce IR through the accumulation of lipid derivatives including DAGs, ceramides and long chain acyl-CoAs in the cytosol, which in turn can interfere with IRS1-PKB signalling [113,114,115,116,117,118].”
From Omega-3 Fatty Acids and Skeletal Muscle Health (2015) · cites this paper as [117]
Decreasing fatty acid flux in humans by pharmacological inhibition of lipolysis or in rats by discontinuing lipid-plus-heparin infusion decreases intramuscular triglyceride concentration and/or accumulation of fatty acid intermediates.
“In contrast, decreasing fatty acid flux in humans via pharmacological inhibition of lipolysis (49) or by discontinuing a lipid-plus-heparin infusion in rats (58) decreases IMTG concentration and/or the accumulation of fatty acid intermediates.”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [58]
Increasing fatty acid flux via lipid-plus-heparin infusion in humans or rodents increases the concentration of intramuscular triglycerides and/or fatty acid intermediates.
“Accordingly, increasing fatty acid flux via a lipid-plus-heparin infusion in humans (23,46) or rodents (58) results in a corresponding increase in the concentration of IMTG and/or fatty acid intermediates.”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [58]
Adipose tissue in obese people is insulin resistant, raising nonesterified fatty acid levels, worsening insulin resistance in muscle, and altering hepatic metabolism.
“Adipose tissue in obese people is insulin resistant, which raises nonesterified fatty acid levels, worsening insulin resistance in muscle 29,33 and altering hepatic metabolism 31 ;”
From Diagnosis and Management of the Metabolic Syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement (2005) · cites this paper as [33]
The disconnection between intramyocellular triglyceride and peripheral insulin action confirms that intramyocellular triglyceride is only a crude marker for the active metabolite (putatively diacylglycerol) that causes fat-induced insulin resistance.
“This disconnection between intramyocellular triglyceride and peripheral insulin action confirms that intra myocellular triglyceride is only a crude marker for the active metabolite (putatively diacylglycerol) that causes fat-induced insulin resistance.38”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [38]
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 [100]
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- Authors
- Yu, C., Chen, Y., Cline, G. W., Zhang, D., Zong, H., Wang, Y., Bergeron, R., Kim, J. K., Cushman, S. W., Cooney, G. J., Atcheson, B., White, M. F., Kraegen, E. W., & Shulman, G. I.
- Affiliations
- Howard Hughes Medical Institute (US)
- National Institutes of Health (US)
- Garvan Institute of Medical Research (AU)
- Joslin Diabetes Center (US)
- Corresponding author
- Shulman, Gerald I.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-12
- Volume
- 277
- Issue
- 52
- Pages
- 50230-50236
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2130850001
- Cited by
- 1,561
- References
- 21
- Citations by year
- 2026: 17 · 2025: 25 · 2024: 36 · 2023: 27 · 2022: 26 · 2021: 47 · 2020: 55 · 2019: 52 · 2018: 56 · 2017: 71 · 2016: 65 · 2015: 65 · 2014: 77 · 2013: 97 · 2012: 101
- FWCI
- 22.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (P30 DK, DK-45735)
- Medical Research Council
- National Health and Medical Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, P30DK045735)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- fatty acids, insulin resistance, skeletal muscle, IRS-1, phosphatidylinositol 3-kinase, protein kinase C theta, diacylglycerol, fatty acyl-CoA, IRS-1 serine phosphorylation, IRS-1 tyrosine phosphorylation, glucose transport, lipid emulsions
- MeSH terms
- Animals, Diglycerides, Fat Emulsions, Intravenous, Fatty Acids, Nonesterified, Insulin, Kinetics, Male, Phosphoproteins, Phosphorylation, Rats, Wistar, Muscle, Skeletal, Phosphotyrosine, Phosphatidylinositol 3-Kinases, Rats, Insulin Receptor Substrate Proteins
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