Induction of insulin resistance in human skeletal muscle cells by downregulation of glycogen synthase protein expression
Abstract
Glycogen synthase (GS) is the rate-limiting enzyme controlling nonoxidative glucose disposal in skeletal muscle. A reduction in GS activity and an impaired insulin responsiveness are characteristic features of skeletal muscle in type 2 diabetes. These properties also exist in human skeletal muscle cell cultures from type 2 diabetic subjects. To determine the effect of an isolated reduction in GS on skeletal muscle insulin action, cultures from nondiabetic subjects were treated with antisense oligonucleotides (ODNs) to GS to interfere with expression of the gene. Treatment with antisense ODNs reduced GS protein expression by 70% compared with control (scrambled) ODNs (P < .01). GS activity measured at 0.01 mmol/L glucose-6-phosphate (G-6-P) was reduced by antisense ODN treatment. The insulin responsiveness of GS was impaired. Insulin also failed to stimulate glucose incorporation into glycogen after antisense ODN treatment. The cellular glycogen content was lower in antisense ODN-treated cells compared with control ODN. The insulin responsiveness of glucose uptake was abolished by antisense ODN treatment. Thus, reductions in GS expression in human skeletal muscle cells lead to impairments in insulin responsiveness and may play an important role in insulin-resistant states.
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Reduced expression of glycogen synthase causes insulin resistance.
“Reduced expression of PKB [40], reduced expression of glycogen synthase [41] or increased expression of GSK-3 [42] causes insulin resistance.”
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Ruzzin, J., Wagman, A. S., & Jensen, J. (2005) · Diabetologia · doi:10.1007/s00125-005-1886-0 · Cited by 243 · see citing works
“Reduced expression of PKB [40], reduced expression of glycogen synthase [41] or increased expression of GSK-3 [42] causes insulin resistance.”
BackgroundImpaired oxidative phosphorylation in skeletal muscle of intrauterine growth-retarded rats
Selak, M. A., Storey, B. T., Peterside, I., & Simmons, R. A. (2003) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00322.2002 · Cited by 162 · see citing works
“Decreased insulin-stimulated glucose uptake resulting in impaired glycogen synthesis in skeletal muscle has been shown to be a major contributing factor to insulin resistance in type 2 diabetes (7, 11, 36, 40, 41, 43, 55).”
BackgroundTaylor, R. P., Parker, G. J., Hazel, M. W., Soesanto, Y., Fuller, W., Yazzie, M. J., & McClain, D. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m707328200 · Cited by 156 · see citing works
Hyperglycemia and Inhibition of Glycogen Synthase in Streptozotocin-treated Mice
Parker, G. J., Taylor, R. P., Jones, D., & McClain, D. A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312139200 · Cited by 84 · see citing works
Al-Khalili, L., Forsgren, M., Kannisto, K., Zierath, J. R., Lönnqvist, F., & Krook, A. (2005) · Diabetologia · doi:10.1007/s00125-005-1741-3 · Cited by 78 · see citing works
“Targeted antisense-mediated reduction of glycogen synthase protein in cultured muscle leads to reduced insulin action [35].”
BackgroundRole of Glycogen Synthase Kinase-3α in Insulin Action in Cultured Human Skeletal Muscle Cells
Ciaraldi, T. P., Nikoulina, S. E., Bandukwala, R., Carter, L., & Henry, R. R. (2007) · Endocrinology · doi:10.1210/en.2006-0932 · Cited by 34 · see citing works
Self-citationGašperíková, D., DEMCÁKOVÁ, E., Ukropec, J., et al. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04301.x · Cited by 10 · see citing works
Chistyakova, O. V., Kuznetsova, L. A., & Leibush, B. N. (2003) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1023/a:1025570315973 · Cited by 1 · see citing works
“This agrees with the literature data that reduction of expression of the GS gene in skeletal muscle leads to the loss of sensitivity of the tissue to insulin [14].”
Schomburg, P. D., Schomburg, I., & Chang, A. (2006) · Springer eBooks · doi:10.1007/3-540-37718-2_11
- Authors
- Park, K. S., Ciaraldi, T. P., Carter, L., Mudaliar, S., Nikoulina, S. E., Webster, N. J. G., & Henry, R. R.
- Affiliations
- University of California San Diego (US)
- Venue
- Metabolism
- Publisher
- Elsevier BV
- Published
- 2000-08
- Volume
- 49
- Issue
- 8
- Pages
- 962-968
- ISSN
- 0026-0495 (ISSN-L)
- OpenAlex
- W2038588802
- Cited by
- 9
- References
- 0
- FWCI
- 0.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Center for Research Resources (MO1 RR00827, M01RR000827)
- 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 › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- glycogen synthase, insulin resistance, skeletal muscle, type 2 diabetes, antisense oligonucleotides, insulin signaling, glucose uptake, glycogen synthesis, glucose-6-phosphate, nonoxidative glucose disposal
- MeSH terms
- Adult, Glucose, Glycogen, Glycogen Synthase, Humans, Insulin, Insulin Resistance, Monosaccharide Transport Proteins, Muscle Proteins, Phosphatidylethanolamines, RNA, Messenger, Down-Regulation, Gene Expression Regulation, Enzymologic, Muscle, Skeletal, ATP-Binding Cassette Transporters, Oligoribonucleotides, Antisense, Gene Silencing, Amino Acid Transport System X-AG, Culture Techniques, Glucose Transporter Type 4
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