Syring Kristen E, Boortz Kayla A, Oeser James K, Ustione Alessandro, Platt Kenneth A, Shadoan Melanie K, McGuinness Owen P, Piston David W, Powell David R, O'Brien Richard M
Department of Molecular Physiology and Biophysics (K.E.S., K.A.B., J.K.O., O.P.M., R.M.O.), Vanderbilt University Medical School, Nashville, Tennessee 37232; Department of Cell Biology and Physiology (A.U., D.W.P.), Washington University School of Medicine, St. Louis, Missouri 63110; and Lexicon Pharmaceuticals Incorporated (K.A.P., M.K.S., D.R.P.), The Woodlands, Texas 77381.
Endocrinology. 2016 Dec;157(12):4534-4541. doi: 10.1210/en.2016-1573. Epub 2016 Oct 18.
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 β-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 α- to β-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.
编码锌转运体8（ZnT8）的溶质载体家族30成员8（SLC30A8）基因多态性与2型糖尿病（T2D）易感性改变相关，且SLC30A8单倍体不足对肥胖人群T2D的发生具有保护作用。SLC30A8主要在胰岛β细胞中表达，但令人惊讶的是，多项基因敲除小鼠研究表明，Slc30a8缺失对葡萄糖耐量或葡萄糖刺激的胰岛素分泌（GSIS）影响甚微。其他多种Slc30a亚型在胰岛中的表达水平较低。我们推测，编码ZnT7的Slc30a7亚型的功能补偿作用限制了Slc30a8缺失对胰岛功能的影响。因此，我们分析了单独缺失Slc30a7或与Slc30a8联合缺失对体内葡萄糖代谢及分离胰岛中GSIS的影响。单独缺失Slc30a7在体内产生了复杂的影响，损害了葡萄糖耐量，降低了葡萄糖刺激后血浆胰岛素水平、肝糖原水平及胰腺胰岛素含量的升高。Slc30a7缺失还影响胰岛形态，增加了胰岛α细胞与β细胞的比例。然而，单独缺失Slc30a7对分离胰岛中的GSIS没有影响，而联合缺失Slc30a7和Slc30a8则消除了GSIS。这些数据表明，去除ZnT7可揭示ZnT8在胰岛中的功能，这意味着ZnT8可能通过在其他低水平表达的组织中的作用而非通过对胰岛功能的影响来影响T2D易感性。
