Barragán-Álvarez Carla P, Padilla-Camberos Eduardo, Díaz Nestor F, Cota-Coronado Agustín, Hernández-Jiménez Claudia, Bravo-Reyna Carlos C, Díaz-Martínez Nestor E
Biotecnología Médica y Farmacéutica, Centro de Investigación y Asistencia en Tecnología y Diseño del Estado de Jalisco, Guadalajara, Mexico.
Departamento de Fisiología y Desarrollo Celular, Instituto Nacional de Perinatología, Mexico City, Mexico.
Mol Cell Biochem. 2021 Jul;476(7):2703-2718. doi: 10.1007/s11010-021-04114-4. Epub 2021 Mar 5.
The zinc transporter 8 (ZnT8) plays an essential role in zinc homeostasis inside pancreatic β cells, its function is related to the stabilization of insulin hexameric form. Genome-wide association studies (GWAS) have established a positive and negative relationship of ZnT8 variants with type 2 diabetes mellitus (T2DM), exposing a dual and controversial role. The first hypotheses about its role in T2DM indicated a higher risk of developing T2DM for loss of function; nevertheless, recent GWAS of ZnT8 loss-of-function mutations in humans have shown protection against T2DM. With regard to the ZnT8 role in T2DM, most studies have focused on rodent models and common high-risk variants; however, considerable differences between human and rodent models have been found and the new approaches have included lower-frequency variants as a tool to clarify gene functions, allowing a better understanding of the disease and offering possible therapeutic targets. Therefore, this review will discuss the physiological effects of the ZnT8 variants associated with a major and lower risk of T2DM, emphasizing the low- and rare-frequency variants.
锌转运体8（ZnT8）在胰腺β细胞内的锌稳态中起着至关重要的作用，其功能与胰岛素六聚体形式的稳定有关。全基因组关联研究（GWAS）已证实ZnT8变异与2型糖尿病（T2DM）存在正相关和负相关关系，揭示了其双重且具有争议性的作用。关于其在T2DM中作用的最初假设表明，功能丧失会增加患T2DM的风险；然而，最近对人类ZnT8功能丧失突变的GWAS研究表明，其对T2DM具有保护作用。关于ZnT8在T2DM中的作用，大多数研究集中在啮齿动物模型和常见的高风险变异上；然而，已发现人类和啮齿动物模型之间存在相当大的差异，新方法已将低频变异作为阐明基因功能的工具，以便更好地理解该疾病并提供可能的治疗靶点。因此，本综述将讨论与T2DM主要和较低风险相关的ZnT8变异的生理效应，重点关注低频和罕见频率变异。
