Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes.
Open accessAbstract
Glycogen synthase (GS) activity is reduced in skeletal muscle of type 2 diabetes, despite normal protein expression, consistent with altered GS regulation. Glycogen synthase kinase-3 (GSK-3) is involved in regulation (phosphorylation and deactivation) of GS. To access the potential role of GSK-3 in insulin resistance and reduced GS activity in type 2 diabetes, the expression and activity of GSK-3 were studied in biopsies of vastus lateralis from type 2 and nondiabetic subjects before and after 3-h hyperinsulinemic (300 mU x m(-2) x min(-1))-euglycemic clamps. The specific activity of GSK-3alpha did not differ between nondiabetic and diabetic muscle and was decreased similarly after 3-h insulin infusion. However, protein levels of both alpha and beta isoforms of GSK-3 were elevated (approximately 30%) in diabetic muscle compared with lean (P < 0.01) and weight-matched obese nondiabetic subjects (P < 0.05) and were unchanged by insulin infusion. Thus, both basal and insulin-stimulated total GSK-3 activities were elevated by approximately twofold in diabetic muscle. GSK-3 expression was related to in vivo insulin action, as GSK-3 protein was negatively correlated with maximal insulin-stimulated glucose disposal rates. In summary, GSK-3 protein levels and total activities are 1) elevated in type 2 diabetic muscle independent of obesity and 2) inversely correlated with both GS activity and maximally insulin-stimulated glucose disposal. We conclude that increased GSK-3 expression in diabetic muscle may contribute to the impaired GS activity and skeletal muscle insulin resistance present in type 2 diabetes.
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Increased expression of GSK-3 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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“Type II diabetes is characterized by elevated GSK3 activity (Nikoulina et al., 2000).”
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“In type 2 diabetics, GSK3B activity is elevated twofold in both basal muscle and insulin-stimulated muscle (Nikoulina et al. 2000).”
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BackgroundMicroRNA-194 Modulates Glucose Metabolism and Its Skeletal Muscle Expression Is Reduced in Diabetes
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- Authors
- Nikoulina, S. E., Ciaraldi, T. P., Mudaliar, S., Mohideen, P., Carter, L., & Henry, R. R.
- Affiliations
- University of California San Diego (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2000-02-01
- Volume
- 49
- Issue
- 2
- Pages
- 263-271
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2098017074
- Cited by
- 357
- References
- 0
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 8 · 2023: 10 · 2022: 13 · 2021: 24 · 2020: 13 · 2019: 16 · 2018: 17 · 2017: 22 · 2016: 13 · 2015: 12 · 2014: 12 · 2013: 15 · 2012: 10
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (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 › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- glycogen synthase kinase-3, type 2 diabetes, skeletal muscle insulin resistance, glycogen synthase, GSK3α, GSK3β, insulin-stimulated glucose disposal, hyperinsulinemic-euglycemic clamp, vastus lateralis, obesity
- MeSH terms
- Adult, Diabetes Mellitus, Type 2, Glycogen Synthase, Humans, Insulin, Insulin Resistance, Isoenzymes, Middle Aged, Phosphorylation, Reference Values, Calcium-Calmodulin-Dependent Protein Kinases, Muscle, Skeletal, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3
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