Medicine: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin

Reuben J. Shaw, Katja A. Lamia, Debbie Vasquez, Seung-Hoi Koo, Nabeel Bardeesy, Ronald A. DePinho, Marc Montminy, Lewis C. Cantley

Research output: Contribution to journalArticle

1290 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1642-1646
Number of pages5
JournalScience
Volume310
Issue number5754
DOIs
Publication statusPublished - 2005 Dec 9
Externally publishedYes

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Metformin
Therapeutic Uses
AMP-Activated Protein Kinases
Homeostasis
Phosphotransferases
Medicine
Glucose
Gluconeogenesis
Liver
Blood Glucose
Peutz-Jeghers Syndrome
Cyclic AMP Response Element-Binding Protein
Peroxisome Proliferator-Activated Receptors
Protein-Serine-Threonine Kinases
Adenosine Monophosphate
Tumor Suppressor Genes
Hyperglycemia
Protein Kinases
Type 2 Diabetes Mellitus
Small Interfering RNA

ASJC Scopus subject areas

  • General

Cite this

Shaw, R. J., Lamia, K. A., Vasquez, D., Koo, S-H., Bardeesy, N., DePinho, R. A., ... Cantley, L. C. (2005). Medicine: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science, 310(5754), 1642-1646. https://doi.org/10.1126/science.1120781

Medicine : The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. / Shaw, Reuben J.; Lamia, Katja A.; Vasquez, Debbie; Koo, Seung-Hoi; Bardeesy, Nabeel; DePinho, Ronald A.; Montminy, Marc; Cantley, Lewis C.

In: Science, Vol. 310, No. 5754, 09.12.2005, p. 1642-1646.

Research output: Contribution to journalArticle

Shaw, RJ, Lamia, KA, Vasquez, D, Koo, S-H, Bardeesy, N, DePinho, RA, Montminy, M & Cantley, LC 2005, 'Medicine: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin', Science, vol. 310, no. 5754, pp. 1642-1646. https://doi.org/10.1126/science.1120781
Shaw, Reuben J. ; Lamia, Katja A. ; Vasquez, Debbie ; Koo, Seung-Hoi ; Bardeesy, Nabeel ; DePinho, Ronald A. ; Montminy, Marc ; Cantley, Lewis C. / Medicine : The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. In: Science. 2005 ; Vol. 310, No. 5754. pp. 1642-1646.
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