The relative reduction in beta cell mass in many people with T2D likely reflects combinations of: 1) genetic predisposition to lower beta cell mass and/or reduced beta cell function, illustrated by GWAS studies (11, 12); 2) inadequate attainment of beta cell mass during fetal life and childhood (13, 14); 3) beta cell de-differentiation induced by glucotoxicity, lipotoxicity and/or endoplasmic reticulum (ER) stress, all driven by excessive demand for insulin resulting from insulin resistance and excessive caloric intake (15–18); and/or combinations of the above. The gene discussed is INS; the disease is type 2 diabetes mellitus.