The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
Modulation of insulin receptor, insulin receptor substrate-1, and phosphatidylinositol 3-kinase in liver and muscle of dexamethasone-treated rats.
Open accessAbstract
Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. Glucocorticoid treatment is known to produce insulin resistance, but the exact molecular mechanism is unknown. In the present study we have examined the levels and phosphorylation state of the insulin receptor and IRS-1, as well as the association/activation between IRS-1 and PI 3-kinase in the liver and muscle of rats treated with dexamethasone. After dexamethasone treatment (1 mg/kg per d for 5 d), there was no change in insulin receptor concentration in liver of rats as determined by immunoblotting with antibody to the COOH-terminus of the receptor. However, insulin stimulation of receptor autophosphorylation determined by immunoblotting with antiphosphotyrosine antibody was reduced by 46.7 +/- 9.1%. IRS-1 and PI 3-kinase protein levels increased in liver of dexamethasone-treated animals by 73 and 25%, respectively (P < 0.05). By contrast, IRS-1 phosphorylation was decreased by 31.3 +/- 10.9% (P < 0.05), and insulin stimulated PI 3-kinase activity in anti-IRS-1 immunoprecipitates was decreased by 79.5 +/- 11.2% (P < 0.02). In muscle, the changes were less dramatic, and often in opposite direction of those observed in liver. Thus, there was no significant change in insulin receptor level or phosphorylation after dexamethasone treatment. IRS-1 and PI 3-kinase levels were decreased to 38.6 and 65.6%, respectively (P < 0.01 and P < 0.05). IRS-1 phosphorylation showed no significant change in muscle, but insulin-stimulated IRS-1 associated PI 3-kinase was decreased by 41%. Thus, dexamethasone has differential effects on the proteins involved in the early steps in insulin action in liver and muscle. In both tissues, dexamethasone treatment results in a reduction in insulin-stimulated IRS-1-associated P I3-kinase, which may play a role in the pathogenesis of insulin resistance at the cellular level in these animals.
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“GCs were shown to interfere with insulin signalling in vitro and in vivo in rodents in liver [38], adipose tissue [39] and skeletal muscle [40].”
From Low-dose glucocorticoid treatment affects multiple aspects of intermediary metabolism in healthy humans: a randomised controlled trial (2011) · cites this paper as [40]
Experimental — accuracy not yet measuredIn the citing paper
“Dexamethasone-induced insulin resistance does not alter tyrosine phosphorylation of the insulin receptor [18,26]”
In the citing paper
“but inhibits insulin-stimulated IRS-1 associated PI 3-kinase activity [26].”
In the citing paper
“This concentration has previously been reported to induce a state of insulin resistance [16,26].”
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“whereas dexamethasone treatment reduces IRS-1-associated PI 3-kinase activity [26].”
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Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein
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Self-citationInsulin Stimulates the Phosphorylation of the 95,000-Dalton Subunit of Its Own Receptor
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Self-citationPhosphatidylinositol 3′‐kinase is activated by association with IRS‐1 during insulin stimulation.
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Lecker, S. H., Goldberg, A. L., & Mitch, W. E. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006010083 · Cited by 1,234
Lipid-induced insulin resistance: unravelling the mechanism
Samuel, V. T., Petersen, K. F., & Shulman, G. I. (2010) · The Lancet · doi:10.1016/s0140-6736(10)60408-4 · Cited by 1,189
Exercise, Glucose Transport, and Insulin Sensitivity
Goodyear, L. J., & Kahn, B. B. (1998) · Annual Review of Medicine · doi:10.1146/annurev.med.49.1.235 · Cited by 1,056
Insulin Action and the Insulin Signaling Network*
Cheatham, B., & Kahn, C. R. (1995) · Endocrine Reviews · doi:10.1210/edrv-16-2-117 · Cited by 885
Self-citationRegulation of glucose homeostasis by glucocorticoids
Kuo, T., McQueen, A., Chen, T.-C., & Wang, J.-C. (2015) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4939-2895-8_5 · Cited by 723
Metadata
- Authors
- Saad, M. J., Folli, F., Kahn, J. A., & Kahn, C. R.
- Affiliations
- Joslin Diabetes Center (US)
- Brigham and Women's Hospital (US)
- Venue
- Journal of Clinical Investigation
- Published
- 1993-10-01
- Volume
- 92
- Issue
- 4
- Pages
- 2065-2072
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC288376
- OpenAlex
- W1986519087
- Cited by
- 349
- References
- 42
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 8 · 2022: 10 · 2021: 9 · 2020: 14 · 2019: 2 · 2018: 11 · 2017: 10 · 2016: 14 · 2015: 9 · 2014: 15 · 2013: 12 · 2012: 12
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Funders
- Joslin Diabetes Center
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- National Institutes of Health (DK 36836)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 33201, DK36836, R01DK033201, P30DK036836)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- insulin resistance, glucocorticoids, dexamethasone, insulin receptor, IRS-1, phosphatidylinositol 3-kinase, insulin receptor autophosphorylation, IRS-1 phosphorylation, liver, skeletal muscle, insulin signaling, insulin receptor tyrosine kinase, tissue-specific effects, rats, enzyme activity
- MeSH terms
- Amino Acid Sequence, Animals, Antibodies, Dexamethasone, Insulin, Kinetics, Liver, Male, Molecular Sequence Data, Muscles, Peptides, Phosphoproteins, Phosphorylation, Receptor, Insulin, Tyrosine, Immunoblotting, Phosphotransferases (Alcohol Group Acceptor), Phosphotyrosine, Phosphatidylinositol 3-Kinases, Rats, Insulin Receptor Substrate Proteins
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