title: The Zinc Transporter Slc30a8/ZnT8 Is Required in a Subpopulation of Pancreatic α-Cells for Hypoglycemia-induced Glucagon Secretion.
abstract: SLC30A8 encodes a zinc transporter ZnT8 largely restricted to pancreatic islet β- and α-cells, and responsible for zinc accumulation into secretory granules. Although common SLC30A8 variants, believed to reduce ZnT8 activity, increase type 2 diabetes risk in humans, rare inactivating mutations are protective. To investigate the role of Slc30a8 in the control of glucagon secretion, Slc30a8 was inactivated selectively in α-cells by crossing mice with alleles floxed at exon 1 to animals expressing Cre recombinase under the pre-proglucagon promoter. Further crossing to Rosa26:tdRFP mice, and sorting of RFP(+): glucagon(+) cells from KO mice, revealed recombination in ∼ 30% of α-cells, of which ∼ 50% were ZnT8-negative (14 ± 1.8% of all α-cells). Although glucose and insulin tolerance were normal, female αZnT8KO mice required lower glucose infusion rates during hypoglycemic clamps and displayed enhanced glucagon release (p < 0.001) versus WT mice. Correspondingly, islets isolated from αZnT8KO mice secreted more glucagon at 1 mm glucose, but not 17 mm glucose, than WT controls (n = 5; p = 0.008). Although the expression of other ZnT family members was unchanged, cytoplasmic (n = 4 mice per genotype; p < 0.0001) and granular (n = 3, p < 0.01) free Zn(2+) levels were significantly lower in KO α-cells versus control cells. In response to low glucose, the amplitude and frequency of intracellular Ca(2+) increases were unchanged in α-cells of αZnT8KO KO mice. ZnT8 is thus important in a subset of α-cells for normal responses to hypoglycemia and acts via Ca(2+)-independent mechanisms.
authors.affiliation: From the Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Antonia
authors.initials: A
authors.lastname: Solomou
authors.affiliation: From the Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Gargi
authors.initials: G
authors.lastname: Meur
authors.affiliation: From the Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bellomo
authors.affiliation: From the Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hodson
authors.affiliation: From the Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom, the Department of Cell Biology, Institute of Ophthalmology, University College London, Greater London EC1V 9EL, United Kingdom.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Tomas
authors.affiliation: the University Paris Diderot-Paris 7, Unit of Functional and Adaptive Biology (BFA) EAC 7059 CNRS, 75013 Paris, France, and.
authors.forename: Stéphanie Migrenne
authors.initials: SM
authors.lastname: Li
authors.affiliation: the University Paris Diderot-Paris 7, Unit of Functional and Adaptive Biology (BFA) EAC 7059 CNRS, 75013 Paris, France, and.
authors.forename: Erwann
authors.initials: E
authors.lastname: Philippe
authors.affiliation: the Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1 rue Michel-Servet, 1211 Geneva-4, Switzerland.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Herrera
authors.affiliation: the University Paris Diderot-Paris 7, Unit of Functional and Adaptive Biology (BFA) EAC 7059 CNRS, 75013 Paris, France, and.
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.affiliation: From the Section of Cell Biology and Functional Genomics, Division of Diabetes Endocrinology and Metabolism, Department of Medicine, Imperial College London, London W12 0NN, United Kingdom, g.rutter@imperial.ac.uk.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007003:Hypoglycemia / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D008810:Mice, Inbred C57BL; D015032:Zinc / Q000378:metabolism; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; C516348:Slc30a8 protein, mouse; D000075703:Zinc Transporter 8; D005934:Glucagon; D005947:Glucose; D015032:Zinc
keywords: calcium; diabetes; glucagon; secretion; zinc