Journal Article

SLC30A3 Responds to Glucose- and Zinc Variations in ß-Cells and Is Critical for Insulin Production and In Vivo Glucose-Metabolism During ß-Cell Stress

Jessen, Niels, Schmitz, Ole, Rungby, Jørgen, Petersen, Andreas Brønden, Bush, Ashley I., Magnusson, Nils, Tsatsanis, Andrew, Brock, Birgitte, Jeppesen, Johanne Bruun, Wogensen, Lise, Culvenor, Janetta G., Larsen, Agnete, Stoltenberg, Meredin, Smidt, Kamille

2009

Overview

Ion transporters of the Slc30A- (ZnT-) family regulate zinc fluxes into sub-cellular compartments. [beta]-cells depend on zinc for both insulin crystallization and regulation of cell mass. This study examined: the effect of glucose and zinc chelation on ZnT gene and protein levels and apoptosis in [beta]-cells and pancreatic islets, the effects of ZnT-3 knock-down on insulin secretion in a [beta]-cell line and ZnT-3 knock-out on glucose metabolism in mice during streptozotocin-induced [beta]-cell stress. In INS-1E cells 2 mM glucose down-regulated ZnT-3 and up-regulated ZnT-5 expression relative to 5 mM. 16 mM glucose increased ZnT-3 and decreased ZnT-8 expression. Zinc chelation by DEDTC lowered INS-1E insulin content and insulin expression. Furthermore, zinc depletion increased ZnT-3- and decreased ZnT-8 gene expression whereas the amount of ZnT-3 protein in the cells was decreased. Zinc depletion and high glucose induced apoptosis and necrosis in INS-1E cells. The most responsive zinc transporter, ZnT-3, was investigated further; by immunohistochemistry and western blotting ZnT-3 was demonstrated in INS-1E cells. 44% knock-down of ZnT-3 by siRNA transfection in INS-1E cells decreased insulin expression and secretion. Streptozotocin-treated mice had higher glucose levels after ZnT-3 knock-out, particularly in overt diabetic animals. Zinc transporting proteins in [beta]-cells respond to variations in glucose and zinc levels. ZnT-3, which is pivotal in the development of cellular changes as also seen in type 2 diabetes (e.g. amyloidosis in Alzheimer's disease) but not previously described in [beta]-cells, is present in this cell type, up-regulated by glucose in a concentration dependent manner and up-regulated by zinc depletion which by contrast decreased ZnT-3 protein levels. Knock-down of the ZnT-3 gene lowers insulin secretion in vitro and affects in vivo glucose metabolism after streptozotocin treatment.

• Publisher: Public Library of Science
• Subject: Amyloidosis / Apoptosis / Cell Biology/Cell Signaling / Cell Biology/Cellular Death and Stress Responses / Cell Biology/Gene Expression / Diabetes and Endocrinology / Gene expression / Genes / Glucose / Glucose metabolism / Immunohistochemistry / Insulin / Proteins / Streptozocin / Type 2 diabetes / Zinc (Nutrient)