Under conditions in which an adequate transduction signal is present (right panel), insulin binding to the insulin receptor results in the phosphorylation of tyrosine residues (Y) on insulin receptor substrates (IRS-1 and -2), which leads to the activation of PI3K and the subsequent phosphorylation of Akt, which are involved in mediating the metabolic effects of insulin. The transcription factor Foxo1, plays a key role in the regulation of HGP, through the transcriptional control of gluconeogenic enzymes, such as phosphoenolpyruvate carboxykinase (PEPCK). Insulin-mediated Akt phosphorylation of Foxo1 leads to its nuclear exclusion, ubiquitination, and subsequent proteasomal degradation, leading to the decreased PEPCK transcription. In turn, gluconeogenic rates and blood glucose concentrations decrease (14). Under conditions of insulin resistance (HF/HC-diet) (left panel), excess lipid metabolites such as DAG can cause insulin resistance by activating PKCε. The activated PKCε binds to the insulin receptor and inhibits its tyrosine kinase activity. The activation of PKCε may also interfere with the ability of insulin to phosphorylate IRS-2 on tyrosine residues (91). IRE, insulin-responsive element; S, serine; Ub, ubiquitination.