Glycolipotoxicity and the pro-inflammatory cytokine TNF-α convert extracellular stress into pattern recognition receptor (PKR) activation via the second messenger ceramide and activated PKR interacts with the conjugating enzyme Ubc9 to promote SUMOylation-dependent stabilization of p53, whose enhanced transcriptional activity leads to cell cycle arrest and disrupts β-cell proliferation, thereby contributing to the progression of T2DM. The gene discussed is EIF2AK2; the disease is type 2 diabetes mellitus.