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SLC30A8 encodes a zinc transporter ZnT8 largely restricted to pancreatic islet beta- and alpha-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 alpha-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 approximately 30% of alpha-cells, of which approximately 50% were ZnT8-negative (14 +/- 1.8% of all alpha-cells). Although glucose and insulin tolerance were normal, female alphaZnT8KO mice required lower glucose infusion rates during hypoglycemic clamps and displayed enhanced glucagon release (p < 0.001) versus WT mice. Correspondingly, islets isolated from alphaZnT8KO 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 alpha-cells versus control cells. In response to low glucose, the amplitude and frequency of intracellular Ca(2+) increases were unchanged in alpha-cells of alphaZnT8KO KO mice. ZnT8 is thus important in a subset of alpha-cells for normal responses to hypoglycemia and acts via Ca(2+)-independent mechanisms.

Original publication

DOI

10.1074/jbc.M115.645291

Type

Journal article

Journal

J Biol Chem

Publication Date

2015

Volume

290

Pages

21432 - 21442

Keywords

Animals Cation Transport Proteins/analysis/genetics/*metabolism Cells, Cultured Female Gene Deletion Glucagon/*metabolism Glucagon-Secreting Cells/cytology/*metabolism Glucose/metabolism Hypoglycemia/genetics/*metabolism Insulin Resistance Mice, Inbred C57BL Zinc/metabolism Zinc Transporter 8 calcium diabetes glucagon secretion zinc