Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion.
The Slc30a8 gene encodes the islet-specific zinc transporter ZnT-8, which provides zinc for insulin-hexamer formation. Polymorphic variants in amino acid residue 325 of human ZnT-8 are associated with altered susceptibility to Type 2 diabetes and ZnT-8 autoantibody epitope specificity changes in Type 1 diabetes. To assess the physiological importance of ZnT-8, mice carrying a Slc30a8 exon 3 deletion were analysed histologically and phenotyped for energy metabolism and pancreatic hormone secretion. No gross anatomical or behavioural changes or differences in body weight were observed between wild-type and ZnT-8-/- mice, and ZnT-8-/- mouse islets were indistinguishable from wild-type in terms of their numbers, size and cellular composition. However, total zinc content was markedly reduced in ZnT-8-/- mouse islets, as evaluated both by Timm's histochemical staining of pancreatic sections and direct measurements in isolated islets. Blood glucose levels were unchanged in 16-week-old, 6 h fasted animals of either gender; however, plasma insulin concentrations were reduced in both female (approximately 31%) and male (approximately 47%) ZnT-8-/- mice. Intraperitoneal glucose tolerance tests demonstrated no impairment in glucose clearance in male ZnT-8-/- mice, but glucose-stimulated insulin secretion from isolated islets was reduced approximately 33% relative to wild-type littermates. In summary, Slc30a8 gene deletion is accompanied by a modest impairment in insulin secretion without major alterations in glucose metabolism.
Pound
Lynley D
LD
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN 37232, USA.
Sarkar
Suparna A
SA
Benninger
Richard K P
RK
Wang
Yingda
Y
Suwanichkul
Adisak
A
Shadoan
Melanie K
MK
Printz
Richard L
RL
Oeser
James K
JK
Lee
Catherine E
CE
Piston
David W
DW
McGuinness
Owen P
OP
Hutton
John C
JC
Powell
David R
DR
O'Brien
Richard M
RM
D000818:Animals; D001786:Blood Glucose; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017384:Sequence Deletion; D015032:Zinc / Q000378:metabolism; D000075703:Zinc Transporter 8
D001786:Blood Glucose; D027682:Cation Transport Proteins; D007328:Insulin; C516348:Slc30a8 protein, mouse; D000075703:Zinc Transporter 8; D015032:Zinc