Zinc transporters and their role in the pancreatic ß-cell

Zinc is an essential nutrient with tremendous importance for human health, and zinc deficiency is a severe risk factor for increased mortality and morbidity. As abnormal zinc homeostasis causes diabetes, and because the pancreatic beta-cell contains the highest zinc content of any known cell type, it is of interest to know how zinc fluxes are controlled in beta-cells. The understanding of zinc homeostasis has been boosted by the discovery of multiprotein families of zinc transporters, and one of them zinc transporter 8 (ZnT8) is abundantly and specifically expressed in the pancreatic islets of Langerhans. In this review, we discuss the evidence for a physiological role of ZnT8 in the formation of zinc-insulin crystals, the physical form in which most insulin is stored in secretory granules. In addition, we cross-examine this information, collected in genetically modified mouse strains, to the knowledge that genetic variants of the human ZnT8 gene predispose to the onset of type 2 diabetes and that epitopes on the ZnT8 protein trigger autoimmunity in patients with type 1 diabetes. The overall conclusion is that we are still at the dawn of a complete understanding of how zinc homeostasis operates in normal beta-cells and how abnormalities lead to beta-cell dysfunction and diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00199.x, 2012)