Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States.
Department of College of Veterinary Medicine, Cornell University, Ithaca, New York, United States.
Am J Physiol Endocrinol Metab. 2024 Jan 1;326(1):E92-E105. doi: 10.1152/ajpendo.00117.2023. Epub 2023 Nov 29.
Zinc is an essential component of the insulin protein complex synthesized in β cells. The intracellular compartmentalization and distribution of zinc are controlled by 24 transmembrane zinc transporters belonging to the ZnT or Zrt/Irt-like protein (ZIP) family. Downregulation of has been reported in pancreatic islets of patients with type 2 diabetes (T2D) as well as mouse models of high-fat diet (HFD)- or db/db-induced obesity. Our previous studies observed mild hyperinsulinemia in mice with whole body knockout of ( KO). Based on our current secondary data analysis from an integrative single-cell RNA-seq dataset of human whole pancreatic tissue, (coding ZIP14) is the only other zinc transporter expressed abundantly in human β cells besides well-known zinc transporter (coding ZnT8). In the present work, using pancreatic β cell-specific knockout of (β- KO), we investigated the role of SLC39A14/ZIP14-mediated intracellular zinc trafficking in glucose-stimulated insulin secretion and subsequent metabolic responses. Glucose-stimulated insulin secretion, zinc concentrations, and cellular localization of ZIP14 were assessed using in vivo, ex vivo, and in vitro assays using β- KO, isolated islets, and murine cell line MIN6. Metabolic evaluations were done on both chow- and HFD-fed mice using time-domain nuclear magnetic resonance and a comprehensive laboratory animal monitoring system. ZIP14 localizes on the endoplasmic reticulum regulating intracellular zinc trafficking in β cells and serves as a negative regulator of glucose-stimulated insulin secretion. Deletion of resulted in greater glucose-stimulated insulin secretion, increased energy expenditure, and shifted energy metabolism toward fatty acid utilization. HFD caused β- KO mice to develop greater islet hyperplasia, compensatory hyperinsulinemia, and mild insulin resistance and hyperglycemia. This study provided new insights into the contribution of metal transporter ZIP14-mediated intracellular zinc trafficking in glucose-stimulated insulin secretion and subsequent metabolic responses. Metal transporter is downregulated in pancreatic islets of patients with T2D and mouse models of HFD- or db/db-induced obesity. However, the function of ZIP14-mediated intracellular zinc trafficking in β cells is unknown. Our analyses revealed that is the only Zn transporter expressed abundantly in human β cells besides . Within the β cells, ZIP14 is localized on the endoplasmic reticulum and serves as a negative regulator of insulin secretion, providing a potential therapeutic target for T2D.
锌是β 细胞中合成的胰岛素蛋白复合物的必需成分。锌的细胞内区室化和分布由 24 种属于 ZnT 或 Zrt/Irt 样蛋白 (ZIP) 家族的跨膜锌转运蛋白控制。已经报道在 2 型糖尿病 (T2D) 患者的胰岛以及高脂肪饮食 (HFD) 或 db/db 诱导肥胖的小鼠模型中下调。我们之前的研究观察到全身性敲除 的小鼠轻度高胰岛素血症（KO）。基于我们当前对人类整个胰腺组织的整合单细胞 RNA-seq 数据集的二次数据分析，除了众所周知的锌转运体 （编码 ZnT8）之外， （编码 ZIP14）是另一种在人类β 细胞中大量表达的锌转运体。在本工作中，使用胰腺β 细胞特异性敲除 （β-KO），我们研究了 SLC39A14/ZIP14 介导的细胞内锌转运在葡萄糖刺激的胰岛素分泌和随后的代谢反应中的作用。使用体内、离体和体外测定，使用 β-KO、分离的胰岛和小鼠细胞系 MIN6 评估葡萄糖刺激的胰岛素分泌、锌浓度和 ZIP14 的细胞定位。使用时域磁共振和综合实验室动物监测系统在 Chow 和 HFD 喂养的小鼠上进行代谢评估。ZIP14 定位于内质网上，调节β 细胞内的锌转运，并作为葡萄糖刺激的胰岛素分泌的负调节剂。 的缺失导致葡萄糖刺激的胰岛素分泌增加、能量消耗增加，并将能量代谢转向脂肪酸利用。HFD 导致 β-KO 小鼠胰岛增生、代偿性高胰岛素血症和轻度胰岛素抵抗和高血糖。这项研究提供了新的见解，即金属转运蛋白 ZIP14 介导的细胞内锌转运在葡萄糖刺激的胰岛素分泌和随后的代谢反应中的作用。在 T2D 患者的胰岛和 HFD 或 db/db 诱导肥胖的小鼠模型中，金属转运蛋白 下调。然而，β 细胞中 ZIP14 介导的细胞内锌转运的功能尚不清楚。我们的分析表明， 除了 之外， 是人类β 细胞中大量表达的唯一 Zn 转运体。在 β 细胞内，ZIP14 定位于内质网上，作为胰岛素分泌的负调节剂，为 T2D 提供了一个潜在的治疗靶点。
