Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade.
Abstract
To examine the mechanism by which free fatty acids (FFAs) induce insulin resistance in vivo, awake chronically catheterized rats underwent a hyperinsulinemic-euglycemic clamp with or without a 5-h preinfusion of lipid/heparin to raise plasma FFA concentrations. Increased plasma FFAs resulted in insulin resistance as reflected by a approximately 35% reduction in the glucose infusion rate (P < 0.05 vs. control). The insulin resistance was associated with a 40-50% reduction in 13C nuclear magnetic resonance (NMR)-determined rates of muscle glycogen synthesis (P < 0.01 vs. control) and muscle glucose oxidation (P < 0.01 vs. control), which in turn could be attributed to a approximately 25% reduction in glucose transport activity as assessed by 2-[1,2-3H]deoxyglucose uptake in vivo (P < 0.05 vs. control). This lipid-induced decrease in insulin-stimulated muscle glucose metabolism was associated with 1) a approximately 50% reduction in insulin-stimulated insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity (P < 0.05 vs. control), 2) a blunting in insulin-stimulated IRS-1 tyrosine phosphorylation (P < 0.05, lipid-infused versus glycerol-infused), and 3) a four-fold increase in membrane-bound, or active, protein kinase C (PKC) theta (P < 0.05 vs. control). We conclude that acute elevations of plasma FFA levels for 5 h induce skeletal muscle insulin resistance in vivo via a reduction in insulin-stimulated muscle glycogen synthesis and glucose oxidation that can be attributed to reduced glucose transport activity. These changes are associated with abnormalities in the insulin signaling cascade and may be mediated by FFA activation of PKC theta.
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Previous 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 [18]
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 [18]
In vivo, infusion of lipid emulsions and heparin in healthy subjects increased plasma NEFA concentrations above the physiological range and was associated with development of insulin resistance mediated by changes in post-receptor insulin signalling.
“In vivo, infusion of lipid emulsions and heparin in healthy subjects increased plasma NEFA concentrations to above the physiological range and were associated with the development of insulin resistance, an effect mediated by changes in post-receptor insulin signalling [149, 150, 151].”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [151]
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 [62]
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 [62]
Findings on insulin signaling and action have been replicated in animal studies.
“These findings have been replicated in animal studies (rodents and rats), further expanding our understanding of the defect involving insulin signaling and action (Griffin et al., 1999; Shulman, 2014; Szendroedi et al., 2014).”
From Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging (2020) · cites this paper as Griffin et al., 1999
Infusion of lipid and heparin or heparin for 5 h causes insulin resistance in muscles associated with accumulation of intracellular diacylglycerol and specific activation of PKCθ.
“Similarly, infusion of lipid and heparin or heparin for 5 h caused insulin resistance in muscles that was associated with accumulation of intracellular diacylglycerol and specific activation of PKCθ.37”
From Lipid-induced insulin resistance: unravelling the mechanism (2010) · cites this paper as [37]
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 [77]
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Self-citationActivation of Toll-like receptor 4 is associated with insulin resistance in adipocytes
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Mechanism of Insulin Resistance in A-ZIP/F-1 Fatless Mice
Kim, J. K., Gavrilova, O., Chen, Y., Reitman, M. L., & Shulman, G. I. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8456 · Cited by 443 · see citing works
Self-citationInsulin resistance as the core defect in type 2 diabetes mellitus
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A futile metabolic cycle activated in adipocytes by antidiabetic agents
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Structure, Activation, and Biology of Calpain
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Protein Kinase C θ Inhibits Insulin Signaling by Phosphorylating IRS1 at Ser1101
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- Authors
- Griffin, M. E., Marcucci, M. J., Cline, G. W., Bell, K., Barucci, N., Lee, D., Goodyear, L. J., Kraegen, E. W., White, M. F., & Shulman, G. I.
- Affiliations
- Yale University (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1999-06-01
- Volume
- 48
- Issue
- 6
- Pages
- 1270-1274
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2043106623
- Cited by
- 1,267
- References
- 8
- Citations by year
- 2026: 15 · 2025: 18 · 2024: 21 · 2023: 18 · 2022: 29 · 2021: 23 · 2020: 26 · 2019: 32 · 2018: 38 · 2017: 32 · 2016: 35 · 2015: 69 · 2014: 51 · 2013: 56 · 2012: 64
- FWCI
- 13.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- 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
- 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, protein kinase C theta, insulin signaling, skeletal muscle, muscle glycogen synthesis, glucose transport, IRS-1, PI3-kinase, IRS-1 tyrosine phosphorylation, hyperinsulinemic-euglycemic clamp, lipid infusion
- MeSH terms
- Protein Kinase C-theta, Animals, Deoxyglucose, Enzyme Activation, Fatty Acids, Nonesterified, Insulin, Insulin Resistance, Isoenzymes, Male, Magnetic Resonance Spectroscopy, Phosphoproteins, Phosphorylation, Protein Kinase C, Tyrosine, Signal Transduction, Zinc Fingers, Rats, Sprague-Dawley, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Rats, Insulin Receptor Substrate Proteins
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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