Figure 1: Model of zinc toxicity and prevention in Type-1 Diabetes We hypothesize that ZnT5 and ZnT8 mediate Zn2+ accumulation in secretory granules. The immune cell response injures β-cells causing Zn2+ release from granules, and re-uptake, through Ca2+ channels, in neighboring β-cells. Additionally, the ROS may oxidize metallothionein causing Zn2+ release. The resulting increased [Zn2+]i may cause direct inhibition of mitochondria, and GAPDH, or their indirect inhibition by a reduction in NAD+ levels induced by the NAD+ catabolizing enzyme SIRT1. Pyruvate, nicotinamide, and sirtuin inhibition prevent NAD+ loss and glycolytic inhibition. Black = Toxic, Gray = Therapeutic.