Contraction inhibits insulin-stimulated insulin receptor substrate-1/2-associated phosphoinositide 3-kinase activity, but not protein kinase B activation or glucose uptake, in rat muscle
Open accessAbstract
The initial stages of insulin-stimulated glucose uptake are thought to involve tyrosine phosphorylation of insulin receptor substrates (IRSs), which recruit and activate phosphoinositide 3-kinase (PI 3-kinase), leading to the activation of protein kinase B (PKB) and other downstream effectors. In contrast, contraction stimulates glucose uptake via a PI 3-kinase-independent mechanism. The combined effects of insulin and contraction on glucose uptake are additive. However, it has been reported that contraction causes a decrease in insulin-stimulated IRS-1-associated PI 3-kinase activity. To investigate this paradox, we have examined the effects of contraction on insulin-stimulated glucose uptake and proximal insulin-signalling events in isolated rat epitrochlearis muscle. Stimulation by insulin or contraction produced a 3-fold increase in glucose uptake, with the effects of simultaneous treatment by insulin and contraction being additive. Wortmannin completely blocked the additive effect of insulin in contracting skeletal muscle, indicating that this is a PI 3-kinase-dependent effect. Insulin-stimulated recruitment of PI 3-kinase to IRS-1 was unaffected by contraction; however, insulin produced no discernible increase in PI 3-kinase activity in IRS-1 or IRS-2 immunocomplexes in contracting skeletal muscle. Consistent with this, contraction inhibited insulin-stimulated p70S6K activation. In contrast, insulin-stimulated activation of PKB was unaffected by contraction. Thus, in contracting skeletal muscle, insulin stimulates glucose uptake and activates PKB, but not p70S6K, by a PI 3-kinase-dependent mechanism that is independent of changes in IRS-1- and IRS-2-associated PI 3-kinase activity.
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PI3 kinase inhibitor wortmannin inhibits insulin but not contraction-stimulated glucose uptake.
“1) PI3 kinase inhibitor wortmannin inhibits insulin but not contraction-stimulated glucose uptake. Contraction does not promote IRS-1 autophosphorylation or increase PI3 kinase activity [103-106].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [104]
Contraction does not promote IRS-1 autophosphorylation or increase PI3 kinase activity.
“1) PI3 kinase inhibitor wortmannin inhibits insulin but not contraction-stimulated glucose uptake. Contraction does not promote IRS-1 autophosphorylation or increase PI3 kinase activity [103-106].”
From AMPK and Exercise: Glucose Uptake and Insulin Sensitivity (2013) · cites this paper as [104]
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- Authors
- WHITEHEAD, J. P., SOOS, M. A., ASLESEN, R., O'RAHILLY, S., & JENSEN, J.
- Affiliations
- University of Cambridge (GB)
- University of Oslo (NO)
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QR, U.K.
- National Institute of Occupational Health (NO)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 2000-07-25
- Volume
- 349
- Issue
- 3
- Pages
- 775-781
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1221204
- OpenAlex
- W191749779
- Cited by
- 48
- References
- 52
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2014: 3 · 2013: 1 · 2012: 3
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- muscle contraction, insulin signaling, IRS-1, insulin receptor substrate 2, phosphatidylinositol 3-kinase, Akt, p70S6K, glucose uptake, skeletal muscle, epitrochlearis muscle, wortmannin, tyrosine phosphorylation
- MeSH terms
- Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Enzyme Activation, Glucose, Insulin, Male, Muscle Contraction, Phosphoproteins, Phosphorylation, Proto-Oncogene Proteins, Rats, Wistar, Protein Serine-Threonine Kinases, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Intracellular Signaling Peptides and Proteins, Proto-Oncogene Proteins c-akt, Rats, Insulin Receptor Substrate Proteins
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