Novel concepts in insulin regulation of hepatic gluconeogenesis

Am J Physiol Endocrinol Metab. 2003 Oct;285(4):E685-92. doi: 10.1152/ajpendo.00253.2003.


The regulation of hepatic gluconeogenesis is an important process in the adjustment of the blood glucose level, and pathological changes in the glucose production of the liver are a central characteristic in type 2 diabetes. The pharmacological intervention in signaling events that regulate the expression of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and the catalytic subunit glucose-6-phosphatase (G-6-Pase) is regarded as a potential strategy for the treatment of metabolic aberrations associated with this disease. However, such intervention requires a detailed understanding of the molecular mechanisms involved in the regulation of this process. Glucagon and glucocorticoids are known to increase hepatic gluconeogenesis by inducing the expression of PEPCK and G-6-Pase. The coactivator protein PGC-1 has been identified as an important mediator of this regulation. In contrast, insulin is known to suppress both PEPCK and G-6-Pase gene expression by the activation of PI 3-kinase. However, PI 3-kinase-independent pathways can also lead to the inhibition of gluconeogenic enzymes. This review focuses on signaling mechanisms and nuclear events that transduce the regulation of gluconeogenic enzymes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Diabetes Mellitus, Type 2 / metabolism*
  • Genes, Regulator / physiology
  • Gluconeogenesis / physiology*
  • Glucose-6-Phosphatase / metabolism*
  • Homeostasis / physiology*
  • Humans
  • Insulin / metabolism*
  • Liver / enzymology
  • Liver / metabolism*
  • Liver / physiology
  • Multienzyme Complexes
  • Phosphoenolpyruvate Carboxykinase (ATP) / metabolism*


  • Insulin
  • Multienzyme Complexes
  • Glucose-6-Phosphatase
  • Phosphoenolpyruvate Carboxykinase (ATP)