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Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients
Open accessAbstract
We characterized metabolic and mitogenic signaling pathways in isolated skeletal muscle from well-matched type 2 diabetic and control subjects. Time course studies of the insulin receptor, insulin receptor substrate (IRS)-1/2, and phosphatidylinositol (PI) 3-kinase revealed that signal transduction through this pathway was engaged between 4 and 40 min. Insulin-stimulated (0.6-60 nmol/l) tyrosine phosphorylation of the insulin receptor beta-subunit, mitogen-activated protein (MAP) kinase phosphorylation, and glycogen synthase activity were not altered in type 2 diabetic subjects. In contrast, insulin-stimulated tyrosine phosphorylation of IRS-1 and anti-phosphotyrosine-associated PI 3-kinase activity were reduced 40-55% in type 2 diabetic subjects at high insulin concentrations (2.4 and 60 nmol/l, respectively). Impaired glucose transport activity was noted at all insulin concentrations (0.6-60 nmol/l). Aberrant protein expression cannot account for these insulin-signaling defects because expression of insulin receptor, IRS-1, IRS-2, MAP kinase, or glycogen synthase was similar between type 2 diabetic and control subjects. In skeletal muscle from type 2 diabetic subjects, IRS-1 phosphorylation, PI 3-kinase activity, and glucose transport activity were impaired, whereas insulin receptor tyrosine phosphorylation, MAP kinase phosphorylation, and glycogen synthase activity were normal. Impaired insulin signal transduction in skeletal muscle from type 2 diabetic patients may partly account for reduced insulin-stimulated glucose transport; however, additional defects are likely to play a role.
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“Maintaining the integrity of the IRS-1/PI-3 kinase/Akt pathway is essential for normal insulin-mediated glucose uptake in skeletal muscle ( 26 ).”
From Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes (2009) · cites this paper as [26]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Using the euglycemic insulin clamp with skeletal muscle biopsy, a number of investigators have examined the insulin signal transduction system in human skeletal muscle of type 2 diabetic subjects and consistently demonstrated defects in IRS-1 tyrosine phosphorylation and PI-3 kinase and Akt activation ( 26 , 54 , 55 ).”
From Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes (2009) · cites this paper as [26]
Experimental — accuracy not yet measuredIn the citing paper
“Association of the p85 subunit of PI3K with IRS-1 and activation of PI3K also are greatly attenuated in obese nondiabetic and type 2 diabetic subjects compared with lean healthy controls [7, 165, 166].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [165]
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“Insulin resistance in the PI3K signaling pathway contrasts with an intact stimulation of the MAPK pathway by insulin in insulin-resistant type 2 diabetic and obese nondiabetics individuals [7, 165].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [165]
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“In insulin resistant individuals with T2DM, glucose transport activity is severely impaired [156, 181, 182, 187–189].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [189]
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Metadata
- Authors
- Krook, A., Björnholm, M., Galuska, D., Jiang, X. J., Fahlman, R., Myers, M. G., Wallberg-Henriksson, H., & Zierath, J. R.
- Affiliations
- Karolinska University Hospital (SE)
- Department of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2000-02-01
- Volume
- 49
- Issue
- 2
- Pages
- 284-292
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2124948826
- Cited by
- 375
- References
- 19
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 10 · 2023: 5 · 2022: 5 · 2021: 13 · 2020: 7 · 2019: 6 · 2018: 20 · 2017: 11 · 2016: 11 · 2015: 13 · 2014: 15 · 2013: 12 · 2012: 13
- FWCI
- 8.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- 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 › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- type 2 diabetes, skeletal muscle, insulin signaling, insulin receptor, IRS-1, insulin receptor substrate 2, phosphatidylinositol 3-kinase, glucose transport, mitogen-activated protein kinase, glycogen synthase, tyrosine phosphorylation, insulin resistance
- MeSH terms
- Biological Transport, Diabetes Mellitus, Type 2, Glucose, Glycogen Synthase, Humans, Insulin, Male, Middle Aged, Phosphoproteins, Phosphorylation, Receptor, Insulin, Time Factors, Tyrosine, Signal Transduction, Muscle, Skeletal, Phosphotyrosine, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, Insulin Receptor Substrate Proteins
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