胰岛细胞特异性 ZnT8 基因缺失和由此导致的锌含量损失可显著改善胰岛素分泌。

IF 3.8 3区医学 Q2 CELL BIOLOGY

Molecular and Cellular Endocrinology Pub Date : 2024-09-23 DOI:10.1016/j.mce.2024.112376

Anthony Piro , Yihan Luo , Ziyi Zhang , Wenyue Ye , Fei Kang , Li Xie , Yufeng Wang , Feihan F. Dai , Herbert Y. Gaisano , Jonathan V. Rocheleau , Kacey J. Prentice , Michael B. Wheeler

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引用次数: 0

摘要

锌转运体 8（ZnT8）在胰腺β细胞中高度表达，定位于胰岛素分泌颗粒（ISG），并调节锌的含量。ZnT8基因多态性揭示了ZnT8活性与2型糖尿病（T2D）风险之间的关系，然而，人们对β细胞ZnT8的作用还不甚了解。我们研究了一种β细胞特异性 ZnT8 基因敲除（ZnT8 BKO）小鼠模型。ZnT8 BKO 小鼠的 ZnT8 基因表达明显减少，锌含量也有所降低。在体内，与对照组相比，ZnT8 BKO 小鼠在通过 S961 诱导急性胰岛素抵抗后，血浆胰岛素水平明显升高，葡萄糖耐受性得到改善。葡萄糖刺激离体 ZnT8 BKO 胰岛分泌胰岛素，显示胰岛素分泌能力增强。补锌后，ZnT8 BKO 胰岛与对照胰岛胰岛分泌胰岛素的差异被抵消，这种抑制作用在人体胰岛中得到了证实。这些结果表明，ZnT8 活性的丧失以及随之而来的细胞锌的减少与胰岛素分泌能力的增强有关。ZnT8 BKO胰岛在补锌后分泌的胰岛素含量减少，这表明ISG释放的锌通常会抑制胰岛素分泌。

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Beta cell specific ZnT8 gene deficiency and resulting loss in zinc content significantly improve insulin secretion

Zinc transporter 8 (ZnT8) is highly expressed in pancreatic beta cells, localizes to insulin secretory granules (ISG), and regulates zinc content. ZnT8 gene polymorphisms have revealed a relationship between ZnT8 activity and type 2 diabetes (T2D) risk, however, the role of beta-cell ZnT8 is not well understood.

A beta cell specific ZnT8 knockout (ZnT8 BKO) mouse model was investigated. ZnT8 BKO islets showed significantly reduced ZnT8 gene expression and reduced zinc content. Compared to controls, ZnT8 BKO mice displayed significantly elevated plasma insulin levels and improved glucose tolerance following acute insulin resistance induced via S961. Glucose stimulated insulin secretion from isolated ZnT8 BKO pancreatic islets revealed enhanced insulin secretion capacity. The difference in insulin secretion between ZnT8 BKO and control islets was negated upon zinc supplementation, and the inhibitory effect of zinc on insulin secretion was confirmed in human islets.

These results indicate that the loss of ZnT8 activity and accompanying reduced cellular zinc are associated with increased insulin secretion capacity. The reduction in secreted insulin content upon zinc supplementation in ZnT8 BKO islets suggests that ISG-released zinc normally tempers insulin secretion.

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来源期刊

Molecular and Cellular Endocrinology 医学-内分泌学与代谢

CiteScore

9.00

自引率

2.40%

发文量

174

审稿时长

42 days

期刊介绍： Molecular and Cellular Endocrinology was established in 1974 to meet the demand for integrated publication on all aspects related to the genetic and biochemical effects, synthesis and secretions of extracellular signals (hormones, neurotransmitters, etc.) and to the understanding of cellular regulatory mechanisms involved in hormonal control.