In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion.
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.
Chimienti
Fabrice
F
DRFMC/SCIB/LAN, UMR-E3 CEA/UJF, CEA Grenoble, 17 rue des Martyrs, 38054 Grenoble CEDEX 9, France. f.chimienti@mellitech.com
Devergnas
Séverine
S
Pattou
François
F
Schuit
Frans
F
Garcia-Cuenca
Rachel
R
Vandewalle
Brigitte
B
Kerr-Conte
Julie
J
Van Lommel
Leentje
L
Grunwald
Didier
D
Favier
Alain
A
Seve
Michel
M
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology; D000075703:Zinc Transporter 8
D027682:Cation Transport Proteins; D007328:Insulin; D011993:Recombinant Fusion Proteins; C516348:Slc30a8 protein, mouse; D000075703:Zinc Transporter 8; D049452:Green Fluorescent Proteins; D005934:Glucagon; D005947:Glucose; D015032:Zinc