FOXO1 and Insulin resistance: In cultured hepatocytes with insulin resistance, r-irisin treatment (20nM) decreases gluconeogenesis via decreasing phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression through the phosphatidylinositol 3-kinase (PI3K)/AKT/Forkhead box protein O1 (FOXO1) signalings, and increases glycogenesis through PI3K/AKT/glycogen synthase kinase 3 (GSK3)/glycogen synthase (GS) signaling cascades (12, 85).