Crucial steps in gluconeogenesis are the conversion of pyruvate to oxaloacetate catalyzed by pyruvate carboxylase (PC); the conversion of oxaloacetate to phosphoenolpyruvate catalyzed by PEPCK; the rate-limiting step catalyzed by fructose-1,6-bisphosphatase (FBP) (Figure 2). The final step, hydrolysis of G6P to glucose by G6Pase, is shared with the glycogenolytic pathway. PGC-1α is an important transcriptional coactivator in the control of gluconeogenic genes and it is strongly induced in the liver of fasting mice. Glucagon, glucocorticoids, and adrenaline induce hepatic glucose output during starvation via increasing PGC-1α levels and activating gluconeogenesis. The concentration of gluconeogenic substrates will also determine glucose production. During the fasted-to-fed transition, insulin suppresses PGC-1α mRNA levels and subsequently reduces gluconeogenic rates and glucose output.
