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Publication
Combined Deletion of Slc30a7 and Slc30a8 Unmasks a Critical Role for ZnT8 in
Glucose-Stimulated Insulin Secretion.
Authors Syring KE, Boortz KA, Oeser JK, Ustione A, Platt KA, Shadoan MK, McGuinness OP,
Piston DW, Powell DR, O'Brien RM
Submitted By Submitted Externally on 12/21/2016
Status Published
Journal Endocrinology
Year 2016
Date Published 12/1/2016
Volume : Pages 157 : 4534 - 4541
PubMed Reference 27754787
Abstract Polymorphisms in the SLC30A8 gene, which encodes the ZnT8 zinc transporter, are
associated with altered susceptibility to type 2 diabetes (T2D), and SLC30A8
haploinsufficiency is protective against the development of T2D in obese humans.
SLC30A8 is predominantly expressed in pancreatic islet ß-cells, but
surprisingly, multiple knockout mouse studies have shown little effect of
Slc30a8 deletion on glucose tolerance or glucose-stimulated insulin secretion
(GSIS). Multiple other Slc30a isoforms are expressed at low levels in pancreatic
islets. We hypothesized that functional compensation by the Slc30a7 isoform,
which encodes ZnT7, limits the impact of Slc30a8 deletion on islet function. We
therefore analyzed the effect of Slc30a7 deletion alone or in combination with
Slc30a8 on in vivo glucose metabolism and GSIS in isolated islets. Deletion of
Slc30a7 alone had complex effects in vivo, impairing glucose tolerance and
reducing the glucose-stimulated increase in plasma insulin levels, hepatic
glycogen levels, and pancreatic insulin content. Slc30a7 deletion also affected
islet morphology and increased the ratio of islet a- to ß-cells. However,
deletion of Slc30a7 alone had no effect on GSIS in isolated islets, whereas
combined deletion of Slc30a7 and Slc30a8 abolished GSIS. These data demonstrate
that the function of ZnT8 in islets can be unmasked by removal of ZnT7 and imply
that ZnT8 may affect T2D susceptibility through actions in other tissues where
it is expressed at low levels rather than through effects on pancreatic islet
function.




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