In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion
In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion
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DOI：
10.1242/jcs.03164
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发表时间：
2006-10-15
影响因子：
4
通讯作者：
Seve, Michel
中科院分区：
文献类型：
--
作者：
Chimienti, Fabrice;Devergnas, Severine;Seve, Michel
分泌胰岛素的胰腺β细胞富含锌。在这些细胞中，锌-胰岛素在分泌囊泡内结晶需要锌。分泌性锌也被认为分别是胰腺α和β细胞中胰高血糖素和胰岛素分泌的旁分泌和自分泌调节剂。然而，人们对含胰岛素囊泡中锌积累的分子机制知之甚少。我们之前发现了一种胰腺特异性锌转运蛋白 ZnT-8，它与培养的 β 细胞中的胰岛素共定位。在本文中，我们研究了它在人胰岛细胞中的定位，及其对细胞锌含量和胰岛素分泌的影响。在人胰岛细胞中，ZnT-8 仅在产生胰岛素的 β 细胞中表达，并与这些细胞中的胰岛素共定位。 ZnT-8 过表达刺激胰岛素分泌 INS-1E 细胞中锌的积累并增加细胞内锌总量。此外，与对照细胞相比，ZnT-8 过表达细胞表现出增强的葡萄糖刺激胰岛素分泌，仅针对高葡萄糖挑战，即。 e. > 10 mM 葡萄糖。总而言之，这些数据强烈表明锌转运蛋白 ZnT-8 是胰腺 β 细胞中锌积累和胰岛素分泌调节的关键蛋白。
Insulin-secreting pancreatic beta cells are exceptionally rich in zinc. In these cells, zinc is required for zinc-insulin crystallization within secretory vesicles. Secreted zinc has also been proposed to be a paracrine and autocrine modulator of glucagon and insulin secretion in pancreatic alpha and beta cells, respectively. However, little is known about the molecular mechanisms underlying zinc accumulation in insulin-containing vesicles. We previously identified a pancreas-specific zinc transporter, ZnT-8, which colocalized with insulin in cultured beta cells. In this paper we studied its localization in human pancreatic islet cells, and its effect on cellular zinc content and insulin secretion. In human pancreatic islet cells, ZnT-8 was exclusively expressed in insulin-producing beta cells, and colocalized with insulin in these cells. ZnT-8 overexpression stimulated zinc accumulation and increased total intracellular zinc in insulin-secreting INS-1E cells. Furthermore, ZnT-8-overexpressing cells display enhanced glucose-stimulated insulin secretion compared with control cells, only for a high glucose challenge, i. e. > 10 mM glucose. Altogether, these data strongly suggest that the zinc transporter ZnT-8 is a key protein for both zinc accumulation and regulation of insulin secretion in pancreatic beta cells.