Tumor Necrosis Factor-α Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation
Abstract
Most lifestyle-related chronic diseases are characterized by low-grade systemic inflammation and insulin resistance. Excessive tumor necrosis factor-α (TNF-α) concentrations have been implicated in the development of insulin resistance, but direct evidence in humans is lacking. Here, we demonstrate that TNF-α infusion in healthy humans induces insulin resistance in skeletal muscle, without effect on endogenous glucose production, as estimated by a combined euglycemic insulin clamp and stable isotope tracer method. TNF-α directly impairs glucose uptake and metabolism by altering insulin signal transduction. TNF-α infusion increases phosphorylation of p70 S6 kinase, extracellular signal–regulated kinase-1/2, and c-Jun NH2-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1. These signaling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signaling cascade regulating GLUT4 translocation and glucose uptake. Thus, excessive concentrations of TNF-α negatively regulate insulin signaling and whole-body glucose uptake in humans. Our results provide a molecular link between low-grade systemic inflammation and the metabolic syndrome.
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These signalling effects are associated with impaired phosphorylation of Akt substrate 160, the most proximal step in the canonical insulin signalling cascade regulating GLUT4 translocation and glucose uptake.
“These signalling effects were associated with impaired phosphorylation of Akt substrate 160, the most proximal step identified in the canonical insulin signalling cascade regulating GLUT4 translocation and glucose uptake.”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [44]
Findings on TNF effects on both glucose and fat metabolism provide a direct molecular link between low-grade systemic inflammation and the metabolic syndrome.
“The findings with regard to an effect of TNF on both glucose and fat metabolism provide a direct molecular link between low-grade systemic inflammation and the metabolic syndrome [44, 45].”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [44]
TNF-α infusion increases phosphorylation of p70 S6 kinase, ERK-1/2, and JNK, with increased serine and reduced tyrosine phosphorylation of IRS-1.
“TNF-alpha infusion increased phosphorylation of p70 S6 kinase, extracellular signal-regulated kinase-1/2, and c-Jun NH(2)-terminal kinase, concomitant with increased serine and reduced tyrosine phosphorylation of insulin receptor substrate-1.”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [44]
TNF-α infusion induces insulin resistance in skeletal muscle of healthy humans without an effect on endogenous glucose production.
“When TNF-α was infused into healthy humans, we found that TNF-α induces insulin resistance in skeletal muscle, without an effect on endogenous glucose production.”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [44]
TNF-α directly impairs glucose uptake and metabolism by altering insulin signal transduction.
“TNF-α directly impaired glucose uptake and metabolism by altering insulin signal transduction.”
From Exercise as a Mean to Control Low‐Grade Systemic Inflammation (2008) · cites this paper as [44]
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References 46 · Cited by 627
- Authors
- Plomgaard, P., Bouzakri, K., Krogh-Madsen, R., Mittendorfer, B., Zierath, J. R., & Pedersen, B. K.
- Affiliations
- University of Copenhagen (DK)
- Karolinska Institutet (SE)
- Department of Infectious Diseases and the Copenhagen Muscle Research Centre, The Centre of Inflammation and Metabolism, Rigshospitalet University of Copenhagen, Faculty of Health Sciences, Copenhagen, Denmark
- Washington University in St. Louis (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-10-01
- Volume
- 54
- Issue
- 10
- Pages
- 2939-2945
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2048488935
- Semantic Scholar
- 51e4cf3e7fd0760935554ca26738f902ac429f30
- Cited by
- 627
- References
- 46
- Citations by year
- 2026: 19 · 2025: 31 · 2024: 27 · 2023: 21 · 2022: 30 · 2021: 31 · 2020: 31 · 2019: 23 · 2018: 26 · 2017: 32 · 2016: 30 · 2015: 30 · 2014: 30 · 2013: 35 · 2012: 33
- FWCI
- 23.18
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56341, P30DK056341)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- TNF-α, insulin resistance, skeletal muscle, IRS-1, insulin signaling, low-grade inflammation, metabolic syndrome, glucose uptake, GLUT4 translocation, hyperinsulinemic-euglycemic clamp, MAPK signaling, serine phosphorylation
- MeSH terms
- Adult, Deuterium, Drug Resistance, Glucose, Humans, Insulin, Liver, Male, Phosphorylation, Placebos, Recombinant Proteins, Tumor Necrosis Factor-alpha, Glucose Clamp Technique, Signal Transduction, Muscle, Skeletal, GTPase-Activating Proteins
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