S1PR3 and Insulin resistance: They demonstrated that apoM/S1P protects against the development of insulin resistance in the liver, adipose tissue, and skeletal muscles by activating AKT and AMPK signaling, which are the main signaling pathways and act via S1P1 and/or S1P3 by enhancing mitochondrial functions, perhaps through the upregulation of the SIRT1 protein levels.