ZnT8

ZnT8, or solute carrier family 30 member 8 (SLC30A8), is a zinc transporter protein that belongs to the ZnT family. In humans, ZnT8 is predominantly expressed in pancreatic islet beta cells and localizes to the membranes of insulin secretory granules. Its primary role is to transport Zn2+ from the cytosol into these granules, enriching the granule lumen with zinc, which is required for insulin crystallization, storage as hexamers, and proper secretion. Zinc transport by ZnT8 relies on the electrochemical proton gradient across granule membranes and is part of a broader zinc homeostasis network within beta cells.

The SLC30A8 gene encodes ZnT8 and is located on chromosome 8. A common coding variant, rs13266634, encodes an arginine-to-tryptophan substitution at residue 325 (R325W) and has been associated with type 2 diabetes risk in multiple populations; functional studies show that reduced ZnT8 activity can influence beta‑cell function. Rare loss-of-function variants in SLC30A8 have been reported to confer a degree of protection against type 2 diabetes, a finding that has spurred interest in ZnT8 as a therapeutic target.

ZnT8 is also an autoantigen in autoimmune diabetes. Autoantibodies to ZnT8 (ZnT8A) are detectable in a substantial subset of individuals with type 1 diabetes and can improve diagnostic sensitivity when used alongside other islet autoantibodies such as GAD65 and IA-2.

Disruption of ZnT8 in animal models leads to reduced beta‑cell zinc content, impaired insulin storage, and altered glucose-stimulated secretion, underscoring ZnT8’s role in insulin handling. Despite genetic evidence suggesting that lowering ZnT8 activity might influence diabetes risk, ZnT8 remains a focus of ongoing research for understanding beta‑cell biology and exploring therapeutic strategies.