Insulin and transcription of PEPCK

Just as it is important for the liver and other tissues to produce glucose if blood glucose levels fall, it is also important to reduce glucose production when blood glucose levels are high.  In this regard, PEPCK is regulated both by insulin, which is released when blood glucose levels are high, as well as directly by extacellular glucose. Insulin is a very powerful regulator of PEPCK transcritpion, and can inhibit the stimulatory effects of glucocorticoids, such as dexamethasone, glucacon, retinoic acid, thyroid hormone, retinoic acid and peroxisome proliforation-activated receptor (PPAR) agonists.

A critical protein in the the signaling pathway of insulin is called Foxo1.  Foxo1 is a protein normally found in the nucleus that interacts with another protein transcription factor called PGC-1alpha (peroxisome proliferation-activated receptor gamma coactivator-1alpha).  PGC-1 alpha and Foxo1 are needed to stimulate PEPCK transcription for both glucocorticoids throught the glucocorticoid response element (GRE) as well as glucagon via the cAMP response element (CRE).  Insulin disrupts glucocorticoid and glucagon signalling becauses  it causes Foxo1 to be exluded from the nucleus.  Thus normal up-regulation cannot take place.

High extracellular glucose concentratons will also inhibit PEPCK transcription in a manner that appears to be independent of insulin.  The exact mechanism has not been determined, but it appears that glucose must be actively metabolised to inhibit PEPCK transcription.  Very interestingly, 2-deoxyglucose also very strongly inhibits the upregulation of PEPCK by dexamethasone and cAMP.  I am interested in whether this inhibition of 2-DG transcription will limit the effectiveness of 2-DG as an antiepileptic drug.

The repression of hormone-activated PEPCK gene expression by glucose is insulin-independent but requires glucose metabolism.  Scott DK, O'Doherty RM, Stafford JM, Newgard CB, Granner DK.  J Biol Chem. 1998 Sep 11;273(37):24145-51. [PDF]

Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice. Altomonte J, Richter A, Harbaran S, Suriawinata J, Nakae J, Thung SN, Meseck M, Accili D, Dong H.  Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E718-28 [PDF]
Copyright 2011 Steve Kriegler