title: Regulation and functional effects of ZNT8 in human pancreatic islets.
abstract: Zinc ions are essential for the formation of insulin crystals in pancreatic β cells, thereby contributing to packaging efficiency of stored insulin. Zinc fluxes are regulated through the SLC30A (zinc transporter, ZNT) family. Here, we investigated the effect of metabolic stress associated with the prediabetic state (zinc depletion, glucotoxicity, and lipotoxicity) on ZNT expression and human pancreatic islet function. Both zinc depletion and lipotoxicity (but not glucotoxicity) downregulated ZNT8 (SLC30A8) expression and altered the glucose-stimulated insulin secretion index (GSIS). ZNT8 overexpression in human islets protected them from the decrease in GSIS induced by tetrakis-(2-pyridylmethyl) ethylenediamine and palmitate but not from cell death. In addition, zinc supplementation decreased palmitate-induced human islet cell death without restoring GSIS. Altogether, we showed that ZNT8 expression responds to variation in zinc and lipid levels in human β cells, with repercussions on insulin secretion. Prospects for increasing ZNT8 expression and/or activity may prove beneficial in type 2 diabetes in humans.
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France. bruno.lefebvre@inserm.fr
authors.forename: Bruno
authors.initials: B
authors.lastname: Lefebvre
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vandewalle
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Balavoine
authors.forename: Gurvan
authors.initials: G
authors.lastname: Queniat
authors.forename: Ericka
authors.initials: E
authors.lastname: Moerman
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
authors.forename: Olivier
authors.initials: O
authors.lastname: Le Bacquer
authors.forename: Valery
authors.initials: V
authors.lastname: Gmyr
authors.forename: Valérie
authors.initials: V
authors.lastname: Pawlowski
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.forename: Francois
authors.initials: F
authors.lastname: Pattou
mesh_terms: D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008055:Lipids / Q000494:pharmacology / Q000633:toxicity; D019308:Palmitic Acid / Q000494:pharmacology / Q000633:toxicity; D014162:Transfection; D015032:Zinc / Q000494:pharmacology; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; D002614:Chelating Agents; D008055:Lipids; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D019308:Palmitic Acid; D015032:Zinc