@article{Solomou:2015:10.1074/jbc.M115.645291,
author = {Solomou, A and Meur, G and Bellomo, E and Hodson, DJ and Tomas, A and Li, SM and Philippe, E and Herrera, PL and Magnan, C and Rutter, GA},
doi = {10.1074/jbc.M115.645291},
journal = {J Biol Chem},
pages = {21432--21442},
title = {The Zinc Transporter Slc30a8/ZnT8 Is Required in a Subpopulation of Pancreatic α-Cells for Hypoglycemia-induced Glucagon Secretion.},
url = {http://dx.doi.org/10.1074/jbc.M115.645291},
volume = {290},
year = {2015}
}

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TY  - JOUR
AB  - 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.
AU  - Solomou,A
AU  - Meur,G
AU  - Bellomo,E
AU  - Hodson,DJ
AU  - Tomas,A
AU  - Li,SM
AU  - Philippe,E
AU  - Herrera,PL
AU  - Magnan,C
AU  - Rutter,GA
DO  - 10.1074/jbc.M115.645291
EP  - 21442
PY  - 2015///
SP  - 21432
TI  - The Zinc Transporter Slc30a8/ZnT8 Is Required in a Subpopulation of Pancreatic α-Cells for Hypoglycemia-induced Glucagon Secretion.
T2  - J Biol Chem
UR  - http://dx.doi.org/10.1074/jbc.M115.645291
UR  - https://www.ncbi.nlm.nih.gov/pubmed/26178371
UR  - http://hdl.handle.net/10044/1/42384
VL  - 290
ER  - 

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