The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance
The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance
复制标题
DOI：
10.1172/jci68807
复制
发表时间：
2013-10-01
影响因子：
15.9
通讯作者：
Watada, Hirotaka
中科院分区：
文献类型：
--
作者：
Tamaki, Motoyuki;Fujitani, Yoshio;Watada, Hirotaka
最近的全基因组关联研究表明，溶质载体家族30成员8基因（SLC 30 A8）的常见变异增加了2型糖尿病的易感性。SLC 30 A8编码锌转运蛋白8（ZnT 8），其将锌离子从细胞质递送到胰岛素颗粒中。虽然众所周知，胰岛素颗粒含有大量的锌，但分泌锌的生理作用仍然难以捉摸。在这项研究中，我们产生了β细胞特异性Slc 30 a8缺陷的小鼠（ZnT 8 KO小鼠），并证明了Slc 30 a8缺失和肝脏胰岛素清除之间的意外功能联系。ZnT 8 KO小鼠具有低的外周血胰岛素水平，尽管胰岛素从胰腺β细胞分泌过多。我们还证明了大量的高分泌胰岛素在其第一次通过肝脏时被降解。与这些发现一致，ZnT 8 KO小鼠和携带SLC 30 A8的主要风险等位基因rs 13266634的人类个体表现出增加的胰岛素清除率，如通过c肽/胰岛素比率评估的。此外，我们证明，锌分泌与胰岛素抑制肝脏胰岛素清除通过抑制网格蛋白依赖性胰岛素内吞。我们的研究结果表明，SLC 30 A8调节肝脏胰岛素清除，该系统的遗传失调可能在2型糖尿病的发病机制中发挥作用。
Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers zinc ion from the cytoplasm into insulin granules. Although it is well known that insulin granules contain high amounts of zinc, the physiological role of secreted zinc remains elusive. In this study, we generated mice with beta cell-specific Slc30a8 deficiency (ZnT8KO mice) and demonstrated an unexpected functional linkage between Slc30a8 deletion and hepatic insulin clearance. The ZnT8KO mice had low peripheral blood insulin levels, despite insulin hypersecretion from pancreatic (3 cells. We also demonstrated that a substantial amount of the hypersecreted insulin was degraded during its first passage through the liver. Consistent with these findings, ZnT8KO mice and human individuals carrying rs13266634, a major risk allele of SLC30A8, exhibited increased insulin clearance, as assessed by c-peptide/insulin ratio. Furthermore, we demonstrated that zinc secreted in concert with insulin suppressed hepatic insulin clearance by inhibiting clathrin-dependent insulin endocytosis. Our results indicate that SLC30A8 regulates hepatic insulin clearance and that genetic dysregulation of this system may play a role in the pathogenesis of type 2 diabetes.