Zinc transporters in the endocrine pancreas

Abstract

The pancreas is composed of two types of cells: the exocrine (acinar) cells and endocrine (pancreatic islet) cells. Pancreatic islets have a high content of zinc (Zn) compared to exocrine tissue. Zinc is especially high in the pancreatic β cells, where it is involved in the maturation, synthesis, and secretion of insulin. Zn in the islet is regulated by zinc-buffering proteins such as metallothionein, membrane Zn transporters, and Zn-permeable ion channels such as TRPM3. There are two families of membrane protein Zn transporters: ZnT proteins lower cytosolic Zn by transporting it into organelles or out of cells while ZIP proteins increase cytosolic Zn by transporting zinc from the extracellular fluids or out of organelles into the cytosol. Some zinc transporters play specific roles in influencing insulin maturation, synthesis, and secretion. For example, ZnT8 is predominantly localized to the membranes of secretory granules in the pancreatic β cells where it is involved in incorporating Zn into crystalline structures of insulin. In both type 1 and 2 diabetes, Zn metabolism is altered and there are changes in ZnT8. A polymorphic variant of ZnT8 is associated with increase in the risk of type 2 diabetes while ZnT8 is an autoantigen in type 1 diabetes. The mechanisms by which ZnT8 is regulated and the role of other Zn transporters in pancreatic islet function are topics of much current interest, with potential implications as future therapeutic targets in diabetes.