Selective Glycogen Synthase Kinase 3 Inhibitors Potentiate Insulin Activation of Glucose Transport and Utilization In Vitro and In Vivo
Open accessAbstract
Insulin resistance plays a central role in the development of type 2 diabetes, but the precise defects in insulin action remain to be elucidated. Glycogen synthase kinase 3 (GSK-3) can negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. A limited amount of information is available regarding the utility of highly selective inhibitors of GSK-3 for the modification of insulin action under conditions of insulin resistance. In the present investigation, we describe novel substituted aminopyrimidine derivatives that inhibit human GSK-3 potently (Ki < 10 nmol/l) with at least 500-fold selectivity against 20 other protein kinases. These low molecular weight compounds activated glycogen synthase at ∼100 nmol/l in cultured CHO cells transfected with the insulin receptor and in primary hepatocytes isolated from Sprague-Dawley rats, and at 500 nmol/l in isolated type 1 skeletal muscle of both lean Zucker and ZDF rats. It is interesting that these GSK-3 inhibitors enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30–48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin. Collectively, our results suggest that these selective GSK-3 inhibitors may be useful as acute-acting therapeutics for the treatment of the insulin resistance of type 2 diabetes.
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Pharmacological inhibition of GSK-3 with selective inhibitors can improve insulin sensitivity in insulin-resistant muscles from ZDF rats.
“Pharmacological inhibition of GSK-3 with highly selective, reversible, cell-permeable small molecules can improve insulin sensitivity in insulin-resistant muscles from Zucker diabetic fatty (ZDF) rats [27][28][29].”
GSK-3 inhibitors increase insulin-stimulated glucose transport in epitrochlearis and soleus muscles from insulin-resistant ZDF rats, but not from insulin-sensitive lean Zucker rats.
“GSK-3 inhibitors increased insulin-stimulated glucose transport in epitrochlearis and soleus muscles from insulin-resistant ZDF rats, but not from insulin-sensitive lean Zucker rats [27,28].”
Pharmacological inhibition of GSK-3 increases insulin-stimulated glucose uptake in insulin-resistant skeletal muscles from obese ZDF rats but not in muscle from insulin-sensitive lean ZDF rats.
“Pharmacological inhibition of GSK-3 increases insulin-stimulated glucose uptake in insulin-resistant skeletal muscles from obese ZDF rats but not in muscle from insulin-sensitive lean ZDF rats [27,28].”
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- Henriksen EJ, Kinnick TR, Teachey MK, O'Keefe MP, Ring D, Johnson KW, Harrison SD: Modulation of muscle insulin resistance by selective glyco- gen synthase kinase-3 inhibition in Zucker diabetic fatty rats. Am J Physiol Endocrinol Metab. In press
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- Authors
- Ring, D. B., Johnson, K. W., Henriksen, E. J., Nuss, J. M., Goff, D., Kinnick, T. R., Ma, S. T., Reeder, J. W., Samuels, I., Slabiak, T., Wagman, A. S., Hammond, M.-E. W., & Harrison, S. D.
- Affiliations
- From the Chiron Corporation, Emeryville, California
- Novartis (Switzerland) (CH)
- University of Arizona (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2003-03-01
- Volume
- 52
- Issue
- 3
- Pages
- 588-595
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2109479865
- Cited by
- 532
- References
- 51
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 25 · 2023: 36 · 2022: 42 · 2021: 30 · 2020: 33 · 2019: 31 · 2018: 21 · 2017: 19 · 2016: 20 · 2015: 25 · 2014: 20 · 2013: 29 · 2012: 18
- FWCI
- 6.91
- 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 Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
- Keywords
- glycogen synthase kinase-3, GSK-3 inhibitors, insulin resistance, type 2 diabetes, insulin signaling, glucose transport, glucose utilization, skeletal muscle, aminopyrimidine derivatives, glycogen synthase, Zucker diabetic fatty rats, db/db mice, glucose disposal, hypoglycemia
- MeSH terms
- Aminopyridines, Animals, Biological Transport, Diabetes Mellitus, Drug Synergism, Enzyme Activation, Enzyme Inhibitors, Female, Glucose, Glycogen Synthase, Cricetinae, Humans, Insulin, Insulin Resistance, Male, Mice, Inbred C57BL, Pyridines, Pyrimidines, Rats, Zucker, Receptor, Insulin, Transfection, Gene Expression, CHO Cells, Rats, Sprague-Dawley, Muscle, Skeletal, Hepatocytes, Glycogen Synthase Kinase 3, Mice, Rats
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