Inhibition of GSK-3 Selectively Reduces Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression

Lochhead, Pamela A.; Coghlan, Matthew; Rice, Simon Q.J.; Sutherland, Calum

doi:10.2337/diabetes.50.5.937

Cited by 219Metabolism, Diabetes, and CancerWnt/β-catenin signaling in development and cancerGlycogen Storage Diseases and Myoclonus

Inhibition of GSK-3 Selectively Reduces Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression

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Lochhead, Pamela A., Coghlan, Matthew, Rice, Simon Q.J., Sutherland, Calum·2001·Diabetes

DOI 10.2337/diabetes.50.5.937

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Abstract

A major action of insulin is to regulate the transcription rate of specific genes. The expression of these genes is dramatically altered in type 2 diabetes. For example, the expression of two hepatic genes, glucose-6-phosphatase and PEPCK, is normally inhibited by insulin, but in type 2 diabetes, their expression is insensitive to insulin. An agent that mimics the effect of insulin on the expression of these genes would reduce gluconeogenesis and hepatic glucose output, even in the presence of insulin resistance. The repressive actions of insulin on these genes are dependent on phosphatidylinositol (PI) 3-kinase. However, the molecules that lie between this lipid kinase and the two gene promoters are unknown. Glycogen synthase kinase-3 (GSK-3) is inhibited following activation of PI 3-kinase and protein kinase B. In hepatoma cells, we find that selectively reducing GSK-3 activity strongly reduces the expression of both gluconeogenic genes. The effect is at the level of transcription and is observed with induced or basal gene expression. In addition, GSK-3 inhibition does not result in the subsequent activation of protein kinase B or inhibition of the transcription factor FKHR, which are candidate regulatory molecules for these promoters. Thus, GSK-3 activity is required for basal activity of each promoter. Inhibitors of GSK-3 should therefore reduce hepatic glucose output, as well as increase the synthesis of glycogen from l-glucose. These findings indicate that GSK-3 inhibitors may have greater therapeutic potential for lowering blood glucose levels and treating type 2 diabetes than previously realized.

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Insulin represses expression of the phosphoenolpyruvate carboxykinase and G-6-Pase genes; PEPCK repression occurs by disrupting association of CREB and RNA polymerase II with the PEPCK gene promoter, whereas G-6-P suppression requires PKBα/Akt and FOXO1, whose expression is diminished by GSK-3 inhibition.
“The second liver-specific effect of insulin is to repress the expression of the phosphoenolpyruvate carboxykinase and G-6-Pase genes; the first by disrupting the association of cAMP response element-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter,23 whereas G-6-P suppression requires PKBα/Akt and forkhead transcription factor (FOXO1),24, 25 whose”
From Pancreatic regulation of glucose homeostasis. (2016) · cites this paper as [26]
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Authors: Lochhead, P. A., Coghlan, M., Rice, S. Q. J., & Sutherland, C.
Affiliations: University of Dundee (GB)
Vascular Biology and
GlaxoSmithKline (United Kingdom) (GB)
ORCID: Lochhead, Pamela A.
Coghlan, Matthew
Sutherland, Calum
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2001-05-01
Volume: 50
Issue: 5
Pages: 937-946
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/diabetes.50.5.937
OpenAlex: W2112820874
Cited by: 219
References: 70
Citations by year: 2026: 4 · 2025: 6 · 2024: 4 · 2023: 3 · 2022: 1 · 2021: 7 · 2020: 6 · 2019: 7 · 2018: 6 · 2017: 8 · 2016: 10 · 2015: 4 · 2014: 10 · 2013: 4 · 2012: 10
FWCI: 6.26
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Diabetes (publishedVersion)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (publishedVersion)
Funders: Wellcome Trust
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
Keywords: glycogen synthase kinase-3, glucose-6-phosphatase, phosphoenolpyruvate carboxykinase, gluconeogenesis, type 2 diabetes, insulin resistance, hepatic gene transcription, phosphatidylinositol 3-kinase, Akt, FOXO1, GSK-3 inhibitors, hepatic glucose production, glycogen synthesis
MeSH terms: Forkhead Box Protein O1, Aminophenols, Animals, Blood Glucose, Choline O-Acetyltransferase, Dexamethasone, Diabetes Mellitus, Type 2, DNA-Binding Proteins, Enzyme Inhibitors, Glucose-6-Phosphatase, Humans, Insulin, Liver Neoplasms, Experimental, Maleimides, Nerve Tissue Proteins, Phosphoenolpyruvate Carboxykinase (GTP), Potassium Chloride, Promoter Regions, Genetic, Proto-Oncogene Proteins, Recombinant Proteins, Transcription Factors, Transfection, Tumor Cells, Cultured, Gene Expression Regulation, Enzymologic, Culture Media, Serum-Free, Protein Serine-Threonine Kinases, Calcium-Calmodulin-Dependent Protein Kinases, Lithium Chloride, Phosphatidylinositol 3-Kinases, Glycogen Synthase Kinases, Glycogen Synthase Kinase 3, Proto-Oncogene Proteins c-akt, Rats, Forkhead Transcription Factors

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Inhibition of GSK-3 Selectively Reduces Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression

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