外源补锌与修复锌转运体治疗2型糖尿病的机制研究

Zinc is the key factor to maintain the density and function of the dense core particles of insulin vesicles in pancreatic β-cells. In a previous study, we demonstrated for the first time that the concentration of free zinc in β-cell vesicles of diabetic db/db mice was lower than that of healthy controls by fluorescence resonance energy transfer technique. In the process of diabetes, the defect of zinc and its transporters lead to a decrease in the density of dense core particles in β-cell vesicles, but the mechanism is not clear. Based on these phenomena, we propose a hypothesis that exogenous zinc supplementation or/and restoration of the expression and function of zinc transporters could increase the concentration of free zinc in the vesicles and restore the density of dense core particles, which may have a potential therapeutic effect of diabetes. Using fluorescence imaging, electron microscopy, pharmacological tests, and molecular biology techniques, we are going to test the role of increasing the free concentration of zinc in insulin vesicles of the pancreatic β-cells and to elucidate the molecular mechanism of regulating the density of dense core particles and treating type 2 diabetes, at molecules (zinc transporter mRNAs), cells (pancreatic β-cells), microtissues (pancreatic islets) and animals (guinea pigs and mice) levels. We hope that this study will provide new ideas for the etiology and therapy of type 2 diabetes.

锌离子是维持β细胞囊泡致密核心颗粒密度和功能的关键因子。在前期研究中，我们利用荧光共振能量转移技术首次证明了糖尿病的db/db小鼠β细胞囊泡的游离锌离子浓度低于健康对照组。在糖尿病的进程中，锌离子及其转运体缺陷导致β细胞囊泡致密核心颗粒密度降低，但机制尚不明确。基于这些现象，我们从维持β细胞囊泡致密核心颗粒密度的角度提出假设：病理状态下，补锌或（和）恢复锌离子转运体的表达量和功能，能够增加囊泡游离的锌离子浓度，重建致密核心颗粒密度，以期具有糖尿病治疗效果。我们采用荧光成像、电镜、生物化学和分子生物学技术，拟从分子（锌离子转运体mRNA分子）与细胞（β细胞的胰岛素囊泡）、微组织器官（胰岛）以及动物整体（豚鼠和小鼠）三个层次阐明锌离子调节致密核心颗粒密度和治疗糖尿病的潜在分子机制。本课题将有望为2型糖尿病的病因学和治疗提供新思路。

在小鼠和人类中，锌是维持胰岛β细胞中胰岛素小泡结构和功能的关键因素。在糖尿病的发展过程中，全身缺锌导致β细胞囊泡中电子致密核的形成能力异常，但其机制尚不清楚。我们先前的研究表明，糖尿病db/db小鼠β细胞囊泡中游离锌的浓度低于健康对照组。基于这一现象，我们假设外源性补锌增加了小鼠2型糖尿病模型小鼠囊泡内游离锌的浓度，并恢复了致密核的电子密度。利用荧光成像、透射电子显微镜和药代动力学分析，我们建立了游离锌浓度的增加和致密核心电子密度的成形性增强之间的强烈联系。因此，我们的结果强调了在体外和体内补充锌促进糖尿病db/db小鼠致密核成熟和恢复胰岛素分泌的机制。本研究为研究2型糖尿病的病因和治疗提供了潜在的研究方向。