In addition to its important physiologic roles in host defense responses to microbial pathogens, injury, and stress, the IKK/NF-κB system has emerged as a major driver of etiopathogenesis in many, if not all, of the most serious threats to global human health, including atherosclerosis, autoimmunity, chronic inflammatory diseases, neurodegenerative conditions, type-2 diabetes (T2D) and other metabolic imbalances such as obesity, as well as cancer. This evidence concerns the gene NFKB1 and type 2 diabetes mellitus.