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 journalArticlepeer-review

1557 Citations (Scopus)


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
Issue number5754
Publication statusPublished - 2005 Dec 9
Externally publishedYes

ASJC Scopus subject areas

  • General


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