Effects of a Novel Glycogen Synthase Kinase-3 Inhibitor on Insulin-Stimulated Glucose Metabolism in Zucker Diabetic Fatty (fa/fa) Rats
Open accessAbstract
Defects in liver and muscle glycogen synthesis are major factors contributing to postprandrial hyperglycemia in patients with type 2 diabetes. Therefore, activation of glycogen synthase through inhibition of glycogen synthase kinase (GSK)-3 represents a potential new therapeutic target. To examine this possibility, we performed oral glucose tolerance tests (OGTTs) and euglycemic-insulinemic clamp studies in Zucker diabetic fatty (fa/fa) rats before and after treatment with novel GSK-3 inhibitors. GSK-3 inhibition caused a 41 ± 2% (P < 0.001) and 26 ± 4% (P < 0.05) reduction in the area under the glucose and insulin concentration curves, respectively, during the OGTT. This improvement in glucose disposal could mostly be attributed to an approximate twofold increase in liver glycogen synthesis. In contrast, there was no significant increase in muscle glycogen synthesis despite an approximate threefold activation of muscle glycogen synthase activity. GSK-3 inhibitor treatment increased liver glycogen synthesis about threefold independent of insulin concentration during the clamp studies. In contrast, muscle glucose uptake and muscle glycogen synthesis were independent of drug treatment. GSK-3 inhibitor treatment lowered fasting hyperglycemia in diabetic rats by 6.0 ± 1.3 mmol/l but had no significant effect on glucose disposal during the clamp. In conclusion, GSK-3 inhibition significantly improved oral glucose disposal, mostly by increasing liver glycogen synthesis. These studies suggest that GSK-3 inhibition may represent an important new therapeutic target for treatment of patients with 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].”
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- Authors
- Cline, G. W., Johnson, K., Regittnig, W., Perret, P., Tozzo, E., Xiao, L., Damico, C., & Shulman, G. I.
- Affiliations
- Yale University (US)
- Pharmacology and Preclinical Research, Chiron, Emeryville, California
- Howard Hughes Medical Institute (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2002-10-01
- Volume
- 51
- Issue
- 10
- Pages
- 2903-2910
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2130357785
- Cited by
- 228
- References
- 51
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 6 · 2023: 3 · 2022: 8 · 2021: 10 · 2020: 6 · 2019: 11 · 2018: 7 · 2017: 8 · 2016: 9 · 2015: 12 · 2014: 9 · 2013: 8 · 2012: 10
- FWCI
- 4.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service (P30 DK45735, R01 DK-40936)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK45735, R01-DK40936, R01DK040936, P30DK045735)
- 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 › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- glycogen synthase kinase-3 inhibition, glycogen synthase, liver glycogen synthesis, muscle glycogen synthesis, insulin-stimulated glucose metabolism, glucose disposal, type 2 diabetes, postprandial hyperglycemia, fasting hyperglycemia, oral glucose tolerance, hyperinsulinemic-euglycemic clamp, Zucker diabetic fatty rats
- MeSH terms
- Animals, Diabetes Mellitus, Type 2, Enzyme Inhibitors, Glucose, Glucose Tolerance Test, Glycogen, Hypoglycemic Agents, Imidazoles, Insulin, Liver, Male, Pyridines, Pyrimidines, Rats, Zucker, Glucose Clamp Technique, Muscle, Skeletal, Glycogen Synthase Kinase 3, Rats
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