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First published online 19 September 2006
doi: 10.1242/jcs.03164

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

¹ DRFMC/SCIB/LAN, UMR-E3 CEA/UJF, CEA Grenoble, 17 rue des Martyrs, 38054 Grenoble CEDEX 9, France
² Mellitech, DRFMC/SCIB, 17 rue des Martyrs, 38054 Grenoble CEDEX 9, France
³ Thérapie Cellulaire du Diabète, INSERM ERIT-M 0106 Faculté de Médecine, Place de Verdun, 59045 Lille, France
⁴ Gene Expression Unit, Division of Biochemistry, Katholieke Universiteit Leuven, 3000 Leuven, Belgium
⁵ Laboratoire Canaux Ioniques et Signalisation, DRDC/LCI, CEA Grenoble, 17 rue des Martyrs, 38054 Grenoble CEDEX 9, France

^* Author for correspondence (e-mail: f.chimienti{at}mellitech.com)

Accepted 11 July 2006

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.

Key words: Langerhans islets, Beta cell, Insulin, Insulin secretion, Zinc transport, Zinc

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