In this study, we discovered that knockout of UCHL1 induces neuron-specific insulin resistance, T2D-associated symptoms, and DSN-like defects in Drosophila. Both Drosophila and mammalian studies revealed that UCHL1 regulates insulin signaling by deubiquitinating IRS1. This evidence concerns the gene UCHL1 and Charcot-Marie-Tooth disease type 3.