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.
Copyright 2011 Steve Kriegler