Medicine: The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin Academic Article uri icon

Overview

MeSH Major

  • Glucose
  • Hypoglycemic Agents
  • Liver
  • Metformin
  • Multienzyme Complexes
  • Protein-Serine-Threonine Kinases

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-gamma coactivator 1alpha (PGC-1alpha), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1alpha 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.

publication date

  • December 9, 2005

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3074427

Digital Object Identifier (DOI)

  • 10.1126/science.1120781

PubMed ID

  • 16308421

Additional Document Info

start page

  • 1642

end page

  • 6

volume

  • 310

number

  • 5754