(A) Under normal circumstances, insulin stimulation of the INSR activates apparently independent arms of the signaling pathway: (i) AKT2 activation, phosphorylation of FOXO1, and inhibition of gluconeogenic gene transcription, leading to decreased glucose output, and (ii) activation of SREBP-1c target lipogenic genes, leading to secretion of triglyceride-rich VLDLs (VLDL TG). (B) Mutation in INSR prevents activation of both arms of the pathway, resulting in increased glucose levels without increased TG levels. (C) Mutation in the AKT2 gene impairs inhibition of gluconeogenesis without abolishing the lipogenic effect of insulin, resulting in increased glucose and TG levels. ACC, acetyl-coenzyme A carboxylase; FAS, fatty acid synthase; PEPCK, phosphoenolpyruvate carboxykinase.