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Potential positive and negative consequences of ZnT8 inhibition.
Syring KE, Bosma KJ, Goleva SB, Singh K, Oeser JK, Lopez CA, Skaar EP,
McGuinness OP, Davis LK, Powell DR, O'Brien RM
Submitted Externally on 9/28/2020
The Journal of endocrinology
Volume : Pages
246 : 189 - 205
SLC30A8 encodes the zinc transporter ZnT8. SLC30A8 haploinsufficiency protects
against type 2 diabetes (T2D), suggesting that ZnT8 inhibitors may prevent T2D.
We show here that, while adult chow fed Slc30a8 haploinsufficient and knockout
(KO) mice have normal glucose tolerance, they are protected against diet-induced
obesity (DIO), resulting in improved glucose tolerance. We hypothesize that this
protection against DIO may represent one mechanism whereby SLC30A8
haploinsufficiency protects against T2D in humans and that, while SLC30A8 is
predominantly expressed in pancreatic islet beta cells, this may involve a role
for ZnT8 in extra-pancreatic tissues. Consistent with this latter concept we
show in humans, using electronic health record-derived phenotype analyses, that
the 'C' allele of the non-synonymous rs13266634 SNP, which confers a gain of
ZnT8 function, is associated not only with increased T2D risk and blood glucose,
but also with increased risk for hemolytic anemia and decreased mean corpuscular
hemoglobin (MCH). In Slc30a8 KO mice, MCH was unchanged but reticulocytes,
platelets and lymphocytes were elevated. Both young and adult Slc30a8 KO mice
exhibit a delayed rise in insulin after glucose injection, but only the former
exhibit increased basal insulin clearance and impaired glucose tolerance. Young
Slc30a8 KO mice also exhibit elevated pancreatic G6pc2 gene expression,
potentially mediated by decreased islet zinc levels. These data indicate that
the absence of ZnT8 results in a transient impairment in some aspects of
metabolism during development. These observations in humans and mice suggest the
potential for negative effects associated with T2D prevention using ZnT8
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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
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