The Kinase LKB1 Mediates Glucose Homeostasis in Liver and Therapeutic Effects of Metformin
Open accessAbstract
The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threonine kinase, LKB1, which phosphorylates and activates AMPK [adenosine monophosphate (AMP)–activated protein kinase]. The deletion of LKB1 in the liver of adult mice resulted in a nearly complete loss of AMPK activity. Loss of LKB1 function resulted in hyperglycemia with increased gluconeogenic and lipogenic gene expression. In LKB1-deficient livers, TORC2, a transcriptional coactivator of CREB (cAMP response element–binding protein), was dephosphorylated and entered the nucleus, driving the expression of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1α expression and normalized blood glucose levels in mice with deleted liver LKB1, indicating that TORC2 is a critical target of LKB1/AMPK signals in the regulation of gluconeogenesis. Finally, we show that metformin, one of the most widely prescribed type 2 diabetes therapeutics, requires LKB1 in the liver to lower blood glucose levels.
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Metformin's effects are mediated by activation of LKB1, which regulates AMPK; AMPK phosphorylates TORC2, inactivating it and downregulating gluconeogenic enzyme synthesis.
“These effects are mediated by the activation of an upstream kinase, liver kinase B1 (LKB-1), which in turn regulates the downstream kinase adenosine monophosphatase protein kinase (AMPK). AMPK phosphorylates a transcriptional co-activator, transducer of regulated CREB protein 2 (TORC2), resulting in its inactivation which consequently downregulates transcriptional events that promote synthesis of”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [2]
Metformin acts primarily at the liver by reducing glucose output and secondarily by augmenting glucose uptake in peripheral tissues, chiefly muscle.
“Metformin acts primarily at the liver by reducing glucose output and, secondarily, by augmenting glucose uptake in the peripheral tissues, chiefly muscle.”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [2]
Metformin has been proposed to cause a mild and transient inhibition of mitochondrial complex I which decreases ATP levels and activates AMPK-dependent catabolic pathways, increasing lipolysis and beta-oxidation in white adipose tissue and reducing neoglucogenesis.
“Metformin has been proposed to cause a mild and transient inhibition of mitochondrial complex I which decreases ATP levels and activates AMPK-dependent catabolic pathways [100], increasing lipolysis and ß-oxidation in white adipose tissue [102] and reducing neoglucogenesis [2].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [2]
Most proposed anti-cancer mechanisms of metformin are mainly mediated through AMPK activation, which requires LKB1, a well-known tumor suppressor.
“Most are mainly mediated through AMPK activation which requires LKB1, a well-known tumor suppressor [2].”
From Metformin: An Old But Still the Best Treatment for Type 2 Diabetes (2013) · cites this paper as [2]
The primary mode of action of metformin is through reduced hepatic glucose output.
“The primary mode of action is through reduced hepatic glucose output (80).”
From Diabetes and Cancer (2010) · cites this paper as [80]
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- Authors
- Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S.-H., Bardeesy, N., DePinho, R. A., Montminy, M., & Cantley, L. C.
- Affiliations
- Salk Institute for Biological Studies (US)
- Corresponding author
- Shaw, Reuben J.
- ORCID
- Venue
- Science
- Published
- 2005-12-09
- Volume
- 310
- Issue
- 5754
- Pages
- 1642-1646
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3074427
- OpenAlex
- W2010238890
- Cited by
- 1,950
- References
- 49
- Citations by year
- 2026: 25 · 2025: 32 · 2024: 66 · 2023: 72 · 2022: 81 · 2021: 99 · 2020: 95 · 2019: 96 · 2018: 84 · 2017: 95 · 2016: 109 · 2015: 113 · 2014: 141 · 2013: 115 · 2012: 123
- FWCI
- 28.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA84313, U01CA084313)
- National Institute of General Medical Sciences (GM056203, R01GM056203, GM37828, R37GM037828)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- LKB1, AMPK, glucose homeostasis, gluconeogenesis, TORC2, PGC-1α, metformin, type 2 diabetes, liver, Peutz-Jeghers syndrome, hyperglycemia, lipogenesis, CREB
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Blood Glucose, Diabetes Mellitus, Type 2, Enzyme Activation, Female, Gene Expression Regulation, Gluconeogenesis, Glucose, HeLa Cells, Homeostasis, Humans, Hyperglycemia, Hypoglycemic Agents, Liver, Male, Metformin, Mice, Obese, Multienzyme Complexes, Phosphorylation, Transcription Factors, Signal Transduction, Trans-Activators, Protein Serine-Threonine Kinases, Lipogenesis, Mice, AMP-Activated Protein Kinases
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