Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine.
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
J Endocrinol. 2020 Aug;246(2):189-205. doi: 10.1530/JOE-20-0138.
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 inhibitors.
SLC30A8 编码锌转运蛋白 ZnT8。SLC30A8 杂合不足可预防 2 型糖尿病 (T2D)，这表明 ZnT8 抑制剂可能预防 T2D。我们在此表明，尽管成年杂合不足和敲除 (KO) SLC30A8 小鼠的正常进食葡萄糖耐量正常，但它们可预防饮食诱导的肥胖 (DIO)，从而改善葡萄糖耐量。我们假设这种对 DIO 的保护可能代表 SLC30A8 杂合不足在人类中预防 T2D 的一种机制，并且虽然 SLC30A8 主要在胰岛β细胞中表达，但这可能涉及 ZnT8 在胰腺外组织中的作用。我们在人类中使用电子健康记录衍生的表型分析一致表明，非同义 rs13266634 SNP 的“C”等位基因赋予 ZnT8 功能的获得，不仅与 T2D 风险和血糖增加相关，而且还与溶血性贫血风险增加和平均红细胞血红蛋白 (MCH) 降低相关。在 Slc30a8 KO 小鼠中，MCH 没有改变，但网织红细胞、血小板和淋巴细胞升高。年轻和成年 Slc30a8 KO 小鼠在葡萄糖注射后胰岛素升高延迟，但只有前者表现出基础胰岛素清除率增加和葡萄糖耐量受损。年轻的 Slc30a8 KO 小鼠还表现出胰腺 G6pc2 基因表达升高，这可能是由胰岛锌水平降低介导的。这些数据表明，在发育过程中，ZnT8 的缺失导致某些代谢方面的短暂损害。这些在人类和小鼠中的观察结果表明，使用 ZnT8 抑制剂预防 T2D 可能会产生负面影响。
