A protection from acute and chronic liver injury in experimental animal models, but these hepatoprotective properties have not been fully identified. In the present study, therefore, we examined the effect of Zn deficiency on diabetes-induced hepatic pathogenic damage and apoptosis as well as possible mechanisms. To this end, we treated mice with multiple low-dose streptozotocin to induce a type 1 diabetes. After diabetic and age-matched control mice were treated with and without TPEN for four months, hepatic pathological changes and cell death along with hepatic inflammation, oxidative damage, and insulin-related signaling pathways were examined. In the present study, we have Bortezomib demonstrated the hepatic injury, including inflammatory response, lipid accumulation, and hepatic cell death along with the increased serum hepatic enzyme, in the type 1 diabetic animals. Diabetes-induced hepatic injury was exacerbated by Zn deficiency induced by chronic treatment with TPEN. Nrf2 as an important transcription factor was found to be decreased in the liver of diabetic and Zn deficient groups, and further decreased in the liver of diabetic mice with Zn deficiency. We also found that Zn deficiency exacerbated diabetic inhibition of Akt and GSK-3b phosphorylation along with an up-regulation of Akt negative regulators. The decreased phosphorylation of GSK-3b is accompanied with a significant increase in nuclear accumulation and decrease in cytosolic accumulation of Fyn. Therefore, we concluded that Zn deficiency significantly exacerbates diabetes-induced hepatic damage, which is likely because Zn deficiency exacerbates diabetic downregulation of Nrf2 expression and function by up-regulation of Akt negative regulators. Up-regulated Akt negative regulators down-regulate the phosphorylation of Akt and GSK-3b, leading to Fyn nuclear translocation that exports Nrf2 to cytosol where being degraded, as shown in Fig. 8. Although TPEN is a multi-heavy metal chelator, it has very high affinity for Zn and iron, and very low affinities for other metals such as calcium and magnesium. Zn is the most abundant trace metal in the human body and has long been known to be an essential element for cell metabolism, antioxidation and survival. Zn deficiency will lead to cell metabolic dysfunction and cell death by induction of caspase activation. In the present study we showed that the hepatic Zn level was decrease in TPEN-treated normal mice and further decrease in TPEN-treated diabetic mice. To further confirm our speculation, we further provided experimental evidence that TPEN-treated hepatic cells also showed the induction of apoptotic cell death in a dose-dependent manner and the apoptotic effect of TPEN in the hepatic cells was able to be completely rescued by supplementation of Zn at 30–50 mM, but not at lower level such as 15 mM. The in vitro study suggests that the apoptotic effect of TPEN treatment is mediated by its chelation of Zn, rather than its direct toxicity. Type 1 diabetic patients with the liver disease often have systemic increases of inflammatory cytokines such as TNF-a. Zn deficiency also induces systemic inflammatory response and hepatic injury. Therefore, we assumed that Zn deficiency in diabetic patients might exacerbate hepatic injury. In support of our hypothesis, we demonstrated here that Zn deficiency significantly exacerbated diabetes-induced hepatic inflammation, oxidative stress, lipid accumulation, and hepatic cell death along with the increased serum hepatic enzyme. Our finding is consistent with a previous study that showed the exacerbation of carbon tetrachloride hepatic toxicity by Zn deficiency. Endoplasmic reticulum stress was found to play a critical role in diabetes pathogenesis and diabetes-induced testicular and cardiac apoptosis.