Similarly to what happens in the liver, intramyocellular lipid accumulation (particularly DAG) activates the PKCθ isoform that phosphorylates and inactivates IRS1 resulting in impaired insulin-stimulated glucose uptake, contributing to hyperglycemia, increased delivery of glucose to the liver, and hyperinsulinemia [241,242]. The gene discussed is INS; the disease is hyperinsulinism.