In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion

• Published in: Journal of cell science Vol. 119; no. Pt 20; pp. 4199 - 4206
• Main Authors: Chimienti, Fabrice, Devergnas, Séverine, Pattou, François, Schuit, Frans, Garcia-Cuenca, Rachel, Vandewalle, Brigitte, Kerr-Conte, Julie, Van Lommel, Leentje, Grunwald, Didier, Favier, Alain, Seve, Michel
• Format: Journal Article
• Language: English
• Published: England Company of Biologists 15.10.2006
• Subjects: Animals; Biological Transport; Biological Transport - drug effects; Cancer; Cation Transport Proteins; Cation Transport Proteins - genetics; Cation Transport Proteins - metabolism; Cation Transport Proteins - physiology; Cell Line; Cell Membrane; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Survival; Cell Survival - drug effects; Dose-Response Relationship, Drug; Gene Expression; Gene Expression - drug effects; Gene Expression - genetics; Glucagon; Glucagon - metabolism; Glucose; Glucose - pharmacology; Green Fluorescent Proteins; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; HeLa Cells; Humans; Insulin; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Islets of Langerhans; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Life Sciences; Male; Mice; Microscopy, Confocal; Microscopy, Fluorescence; Models, Biological; Recombinant Fusion Proteins; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Secretory Vesicles; Secretory Vesicles - drug effects; Secretory Vesicles - metabolism; Zinc; Zinc - metabolism; Zinc - pharmacology; Zinc Transporter 8; Zinc transport; Langerhans islets; Insulin; Zinc; Beta cell; Insulin secretion
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.03164

Insulin-secreting pancreatic beta cells are exceptionally rich in zinc. In these cells, zinc is required for zinc-insulin crystallization within secretory vesicles. Secreted zinc has also been proposed to be a paracrine and autocrine modulator of glucagon and insulin secretion in pancreatic alpha and beta cells, respectively. However, little is known about the molecular mechanisms underlying zinc accumulation in insulin-containing vesicles. We previously identified a pancreas-specific zinc transporter, ZnT-8, which colocalized with insulin in cultured beta cells. In this paper we studied its localization in human pancreatic islet cells, and its effect on cellular zinc content and insulin secretion. In human pancreatic islet cells, ZnT-8 was exclusively expressed in insulin-producing beta cells, and colocalized with insulin in these cells. ZnT-8 overexpression stimulated zinc accumulation and increased total intracellular zinc in insulin-secreting INS-1E cells. Furthermore, ZnT-8-overexpressing cells display enhanced glucose-stimulated insulin secretion compared with control cells, only for a high glucose challenge, i.e. >10 mM glucose. Altogether, these data strongly suggest that the zinc transporter ZnT-8 is a key protein for both zinc accumulation and regulation of insulin secretion in pancreatic beta cells.