Cited by 357Metabolism, Diabetes, and CancerDiabetes, Cardiovascular Risks, and LipoproteinsAdipokines, Inflammation, and Metabolic Diseases

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Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes.

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Nikoulina, S E, Ciaraldi, T P, Mudaliar, S, Mohideen, P, Carter, L, Henry, R R·2000·Diabetes

DOI 10.2337/diabetes.49.2.263

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Abstract

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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Background
Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus
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“Numerous evidences support a role of elevated GSK-3 as a contributing factor in various pathophysiological states such as insulin resistance, obesity, diabetes, glucose intolerance and dyslipidemia (Eldar-Finkelman et al. 1996, Nikoulina et al. 2000).”
Background
GSK3α phosphorylates dynamin-2 to promote GLUT4 endocytosis in muscle cells
Laiman, J., Hsu, Y.-J., Loh, J., Tang, W., Chuang, M., Liu, H., Yang, W., Chen, B., Chuang, L., Chang, Y., et al. (2022) · The Journal of Cell Biology · doi:10.1083/jcb.202102119 · Cited by 22
“Importantly, higher GSK3 expression and activity have been observed in the skeletal muscle of T2D patients and diabetic mice (Eldar-Finkelman and Krebs, 1997; Nikoulina et al., 2000).”
Background
Silencing of p53 RNA through transarterial delivery ameliorates renal tubular injury and downregulates GSK-3β expression after ischemia-reperfusion injury
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Loss of hnRNP A1 in murine skeletal muscle exacerbates high-fat diet-induced onset of insulin resistance and hepatic steatosis
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“Inhibition of GSK-3 β further contributes to the dephosphorylation and activation of GS (Cross et al., 1995; Nikoulina et al., 2000; Hojlund et al., 2003).”
Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 cooperates with glycogen synthase kinase-3β to regulate osteogenesis of bone-marrow mesenchymal stem cells in type 2 diabetes
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“Its expression is elevated in T2DM models and negatively correlated with whole-body glucose disposal (Nikoulina et al., 2000; Azevedo et al., 2010).”

Authors: Nikoulina, S. E., Ciaraldi, T. P., Mudaliar, S., Mohideen, P., Carter, L., & Henry, R. R.
Affiliations: University of California San Diego (US)
ORCID: Ciaraldi, T P
Mudaliar, S
Henry, R R
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2000-02-01
Volume: 49
Issue: 2
Pages: 263-271
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diabetes.49.2.263
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 › Endocrinology, Diabetes and Metabolism › 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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Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes.

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