GSE195464
Zinc Transporter 8 Haploinsufficiency Protects Against Beta Cell Dysfunction in Type 1 Diabetes by Increasing Mitochondrial Respiration
Zinc transporter 8 (ZnT8) is a major humoral target in human type 1 diabetes (T1D). Polymorphic variants of Slc30A8, which encodes ZnT8, are also associated with protection from T2D, suggesting that ZnT8 might play a role beyond simply being a target of autoimmunity in the pathophysiology of T1D. To begin to investigate this possibility, we transferred a global Slc30a8 null allele to the well-established NOD mouse model of T1D. Unexpectedly, complete loss of ZnT8 accelerated spontaneous T1D, while heterozygosity was partially protective. In vivo and in vitro studies using ZnT8 mutants on a NOD.scid background suggested that the accelerated disease was due to more rampant autoimmunity. Conversely, beta cells in heterozygous animals uniquely displayed increased mitochondrial fitness under mild proinflammatory conditions. In pancreatic beta cells and immune cell populations, Zn2+ plays a key role as a regulator of redox signaling and as an independent secondary messenger. Importantly, Zn2+ also plays a major role in maintaining mitochondrial homeostasis. Our results suggest that regulating mitochondrial fitness by altering intra-islet zinc homeostasis may provide a novel mechanism to modulate T1D pathophysiology. Overall design: RNA-seq of WT, ZnT8+/-, and ZnT8-/- islets with and without treatment of cytokines (6 total conditions).