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.