Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB-binding protein

Nat Med. 2004 Jun;10(6):633-7. doi: 10.1038/nm1050. Epub 2004 May 16.


Hepatic gluconeogenesis is essential for maintenance of normal blood glucose concentrations and is regulated by opposing stimulatory (cyclic adenosine monophosphate, cAMP) and inhibitory (insulin) signaling pathways. The cAMP signaling pathway leads to phosphorylation of cAMP response element-binding (CREB) protein, resulting in recruitment of the coactivators CREB-binding protein (CBP) and p300 and subsequent activation of gluconeogenesis. Insulin signaling leads to phosphorylation of CBP at serine 436, a residue near its CREB-interacting domain, but it is unknown whether this event modulates cAMP signaling. Here, we show in vitro and in 'knock-in' mice that a mutant CBP (S436A) is aberrantly recruited to CREB protein, resulting in inappropriate activation of gluconeogenesis in the fed state and glucose intolerance resulting from increased hepatic glucose production. We propose that insulin signaling may directly regulate many cAMP signaling pathways at the transcriptional level by controlling CBP recruitment.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CREB-Binding Protein
  • Cells, Cultured
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Gluconates
  • Gluconeogenesis / physiology*
  • Glucose / metabolism
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Insulin / metabolism*
  • Islets of Langerhans / metabolism
  • Liver / cytology
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Transgenic
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Second Messenger Systems / physiology
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*


  • Cyclic AMP Response Element-Binding Protein
  • Gluconates
  • Insulin
  • Nuclear Proteins
  • Trans-Activators
  • Cyclic AMP
  • CREB-Binding Protein
  • CREBBP protein, human
  • Crebbp protein, mouse
  • Glucose
  • gluconic acid