Pediatrics & Therapeutics
Open Access

Abstract

Antagonistic Effects of Insulin Signaling and Glucagon Signaling on Controlling Hepatic Gluconeogenic Gene Expression

Evan Chang and Ling He

With the worldwide epidemics of obesity and diabetes, there is an urgent need for action at the global and national levels to prevent and to treat these metabolic disorders. Inappropriate hepatic glucose production is the major cause of hyperglycemia in obese and diabetic patients. In this mini-review, we summarize the antagonistic effects of insulin signaling and glucagon signaling on controlling gene expression related to hepatic glucose production through CREB co-activators and FOXO1. In the fasted state, phosphorylation of CREB at S133 recruits CBP/P300 and CRTC2 to CREB, leading to the formation of CREB co-activators complex. CREB and P300 also upregulate FOXO1 gene expression. CREB co-activators together with FOXO1 drive gluconeogenic gene expression to maintain euglycemia. In the fed state, insulin suppresses gluconeogenic gene expression through the phosphorylation of CBP, which results in the disassembly of CREB-CBP-CRTC2 complex, furthermore, phosphorylation of CRTC2 and FOXO1 by insulin excludes CRTC2 and FOXO1 from nucleus and promotes their degradation in cytoplasm.