Figure 3. Schematic representation of pathways involved in hepatic insulin resistance.

Insulin activates the insulin receptor tyrosine kinase which subsequently tyrosine phosphorylates IRS1 and 2. Through a set of intermediary steps, this leads to activation of Akt2. Akt2 can promote glycogen synthesis (not shown), suppress gluconeogenesis and activate de novo lipogenesis (DNL). This central signaling pathway is connected to multiple other cellular pathways that are designated by numbers 1–3. 1) The green shaded areas represent mechanisms for lipid induced insulin resistance, notably diacylglycerol mediated activation of PKCε and subsequent impairment of insulin signaling, as well as ceramide mediated increases in PP2A and increased sequestration of Akt2 by PKCζ. Impaired Akt2 activation limits the inactivation of FOXO1 and allows for increased expression of key gluconeogenesis enzymes. Impaired Akt2 activity also decreases insulin mediated glycogen synthesis (not depicted). 2) The yellow areas depict several intracellular inflammatory pathways, notably the activation of IKK, which may impact ceramide synthesis and the activation of JNK1, which may impair lipogenesis. 3) The pink area depicts that activation of the UPR that can lead to increased lipogenesis, via XBP1s and also increased gluconeogenesis via C/EBP. The ER membranes also contain key lipogenic enzymes and give rise to lipid droplets. Proteins that regulate the release from these droplets (e.g. ATGL and PNPLA3) may modulate the concentration of key lipid intermediates in discrete cell compartments.