The zinc transporter Slc30a8/ZnT8 is required in a subpopulation of pancreatic α;-cells for hypoglycemia-induced glucagon secretion

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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 diabetesrisk 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 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 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.

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APA

Solomou, A., Meur, G., Bellomo, E., Hodson, D. J., Tomas, A., Li, S. M., … Rutter, G. A. (2015). The zinc transporter Slc30a8/ZnT8 is required in a subpopulation of pancreatic α;-cells for hypoglycemia-induced glucagon secretion. Journal of Biological Chemistry, 290(35), 21432–21442. https://doi.org/10.1074/jbc.M115.645291

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