Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion.
Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion.
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DOI：
10.1042/bj20090530
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发表时间：
2009-07-15
期刊：
影响因子：
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通讯作者：
O'Brien RM
中科院分区：
文献类型：
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作者：
Pound LD;Sarkar SA;Benninger RK;Wang Y;Suwanichkul A;Shadoan MK;Printz RL;Oeser JK;Lee CE;Piston DW;McGuinness OP;Hutton JC;Powell DR;O'Brien RM
Slc30a8基因编码胰岛特异性锌转运蛋白ZnT - 8，它为胰岛素六聚体的形成提供锌。人类ZnT - 8的氨基酸325处的多态性变异与2型糖尿病易感性的改变以及1型糖尿病中ZnT - 8自身抗体表位特异性的变化有关。为了评估ZnT - 8的生理重要性，对携带Slc30a8外显子3缺失的小鼠进行了组织学分析，并对其能量代谢和胰腺激素分泌进行了表型分析。在野生型和ZnT - 8 - / - 小鼠之间未观察到明显的解剖学或行为变化以及体重差异，并且ZnT - 8 - / - 小鼠胰岛在数量、大小和细胞组成方面与野生型无法区分。然而，通过胰腺切片的Timm组织化学染色以及对分离的胰岛进行直接测量发现，ZnT - 8 - / - 小鼠胰岛中的总锌含量显著降低。在16周龄、禁食6小时的雌雄动物中，血糖水平没有变化，然而，雌性（约31%）和雄性（约47%）ZnT - 8 - / - 小鼠的血浆胰岛素浓度均降低。腹腔内葡萄糖耐量试验表明，雄性ZnT - 8 - / - 小鼠的葡萄糖清除没有受损，但从分离的胰岛中葡萄糖刺激的胰岛素分泌相对于野生型同窝小鼠降低了约33%。总之，Slc30a8基因缺失伴随着胰岛素分泌的适度受损，但葡萄糖代谢没有重大改变。
The Slc30a8 gene encodes the islet-specific zinc transporter ZnT-8, which provides zinc for insulin-hexamer formation. Polymorphic variants in amino acid 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 analyzed histologically and phenotyped for energy metabolism and pancreatic hormone secretion. No gross anatomical or behavioral 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 hr fasted animals of either gender, however, plasma insulin concentrations were reduced in both female (~31%) and male (~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 ~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.