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Cited by 375Metabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and LipoproteinsAdipokines, Inflammation, and Metabolic Diseases

Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients

Open access
Krook, A, Björnholm, M, Galuska, D, Jiang, X J, Fahlman, R, Myers, M G, Wallberg-Henriksson, H, Zierath, J R·2000·Diabetes
DOI 10.2337/diabetes.49.2.284
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Abstract

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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Crossref · 10.2337/diabetes.49.2.284

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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.

    “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]

    The paper’s introduction identifies IRS-1 and PI 3-kinase as components of insulin signaling involved in skeletal-muscle glucose transport. Its study summary says reduced PI 3-kinase activity may partly account for reduced insulin-stimulated glucose transport, while additional defects contribute. The cited passages do not establish a role for Akt or show that integrity of the entire pathway is essential for normal uptake. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • In human skeletal muscle of type 2 diabetic subjects, defects in IRS-1 tyrosine phosphorylation and PI-3 kinase and Akt activation are consistently demonstrated.

    “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]

    The Abstract and Results report reduced insulin-stimulated IRS-1 tyrosine phosphorylation and PI 3-kinase activity in skeletal muscle from type 2 diabetic subjects. The Discussion also reports these defects in an earlier clamp study. Our copy does not demonstrate defective Akt activation, and this paper's own experiments used isolated muscle rather than a euglycemic clamp. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

  • Association of p85 subunit of PI3K with IRS-1 and PI3K activation are greatly attenuated in obese nondiabetic and type 2 diabetic subjects compared with lean healthy controls.

    “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]

  • Insulin resistance in the PI3K pathway contrasts with intact insulin stimulation of the MAPK pathway in insulin-resistant type 2 diabetic and obese nondiabetic individuals.

    “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]

  • In insulin-resistant individuals with T2DM, glucose transport activity is severely impaired.

    “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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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.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2000-02-01
Volume
49
Issue
2
Pages
284-292
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/diabetes.49.2.284
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
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 › Epidemiology › 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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