IRS1 and Insulin resistance: Perhaps the most reasonable explanation for these findings is that proteasome deficiency will accumulate the ubiquitinated proteins in ER lumen resulting in ER stress and unfold protein response (UPR) (Cybulsky, 2013; Otoda et al., 2013), which leads to activation of JNK/IRS-1 pathway and subsequent insulin resistance (Ozcan et al., 2004; Nakatani et al., 2005).