@article{Solomou:2016:10.1186/s12986-016-0104-z,
author = {Solomou, A and Philippe, E and Chabosseau, P and Migrenne-Li, S and Gaitan, J and Lang, J and Magnan, C and Rutter, GA},
doi = {10.1186/s12986-016-0104-z},
journal = {Nutrition and Metabolism},
title = {Over-expression of Slc30a8/ZnT8 selectively in the mouse α cell impairs glucagon release and responses to hypoglycemia},
url = {http://dx.doi.org/10.1186/s12986-016-0104-z},
volume = {13},
year = {2016}
}

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TY  - JOUR
AB  - BackgroundThe human SLC30A8 gene encodes the secretory granule-localised zinc transporter ZnT8 whose expression is chiefly restricted to the endocrine pancreas. Single nucleotide polymorphisms (SNPs) in the human SLC30A8 gene have been associated, through genome-wide studies, with altered type 2 diabetes risk. In addition to a role in the control of insulin release, recent studies involving targeted gene ablation from the pancreatic α cell (Solomou et al., J Biol Chem 290(35):21432-42) have also implicated ZnT8 in the control of glucagon release. Up to now, however, the possibility that increased levels of the transporter in these cells may impact glucagon secretion has not been explored.MethodsHere, we use a recently-developed reverse tetracyline transactivator promoter-regulated ZnT8 transgene to drive the over-expression of human ZnT8 selectively in the α cell in adult mice. Glucose homeostasis and glucagon secretion were subsequently assessed both in vivo during hypoglycemic clamps and from isolated islets in vitro.ResultsDoxyclin-dependent human ZnT8 mRNA expression was apparent in both isolated islets and in fluorescence-activated cell sorting- (FACS) purified α cells. Examined at 12 weeks of age, intraperitoneal glucose (1 g/kg) tolerance was unchanged in transgenic mice versus wild-type littermates (n = 8-10 mice/genotype, p > 0.05) and sensitivity to intraperitoneal insulin (0.75U/kg) was similarly unaltered in transgenic animals. In contrast, under hyperinsulinemic-hypoglycemic clamp, a ~45 % (p < 0.001) reduction in glucose infusion rate was apparent, and glucagon release was significantly (~40 %, p < 0.01) impaired, in transgenic mice. Correspondingly, examined in vitro, glucagon secretion was significantly reduced (~30 %, p < 0.05) from transgenic versus control islets at low, stimulatory glucose concentrations (1 mM, p < 0.05) but not at
AU  - Solomou,A
AU  - Philippe,E
AU  - Chabosseau,P
AU  - Migrenne-Li,S
AU  - Gaitan,J
AU  - Lang,J
AU  - Magnan,C
AU  - Rutter,GA
DO  - 10.1186/s12986-016-0104-z
PY  - 2016///
SN  - 0029-6678
TI  - Over-expression of Slc30a8/ZnT8 selectively in the mouse α cell impairs glucagon release and responses to hypoglycemia
T2  - Nutrition and Metabolism
UR  - http://dx.doi.org/10.1186/s12986-016-0104-z
UR  - http://hdl.handle.net/10044/1/34401
VL  - 13
ER  - 

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