 A downstream effect of the ER stress is a significant decrease in insulin-stimulated phosphorylation of tyrosine residues of insulin receptor substrate (IRS-1), which is the substrate for insulin tyrosine kinase (the insulin receptor).C-Jun N-terminal kinase (JNK) is also activated at high levels by IRE-1α, which itself is phosphorylated to become activated in the presence of ER stress.Subsequently, JNK phosphorylates serine residues of IRS-1, and thus inhibits insulin receptor signaling.