Although an activating effect of the identified mutants on the remaining allele cannot be excluded absolutely, an alternative explanation (20) is that a complex interplay between insulin storage and Zn2+ release by β-cells, and downstream effects on target tissues including the liver, results in a bimodal (bell-shaped) dependence of T2D risk on ZnT8 activity. This evidence concerns the gene INS and type 2 diabetes mellitus.