Figure 2. Schematic representation of pathways involved in muscle insulin resistance.

Insulin activates the insulin receptor tyrosine kinase which subsequently tyrosine phosphorylates IRS1. Through a series of intermediary steps, this leads to activation of Akt2. Akt2 activation, via AS160 and Rab-GTPase (not shown), promotes the translocation of GLUT4 containing storage vesicles (GSV’s) to the plasma membrane permitting the entry of glucose into the cell and promotes glycogen synthesis. 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 PKCθ 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 translocation of GSV’s to the plasma membrane resulting in impaired glucose uptake. Impaired Akt2 activity also decreases insulin mediated glycogen synthesis. 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 insulin signaling via serine phosphorylation of IRS1. 3) The pink area depicts that activation of the UPR which under some instances (e.g. acute extreme exercise) may lead to activation of ATF6 and a PGC1α mediated adaptive response. 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.