Purpose

People with diabetes are at high risk of lacrimal gland dysfunction, but the underlying mechanism is not well understood. In this study, we determined how type 1 diabetes mellitus (T1DM) influences circadian homeostasis of the murine extraorbital lacrimal glands (ELGs).

Methods

A T1DM animal model was established by systemic streptozotocin injection in C57BL/6J mice. After 5 weeks, ELGs were collected at 3-h intervals over a 24-h circadian cycle. Total extracted RNA was subjected to high-throughput RNA sequencing, and rhythmic transcriptional data were evaluated using the Jonckheere-Terpstra-Kendall algorithm, Kyoto Encyclopedia of Genes and Genomes pathway analysis, Phase Set Enrichment Analysis, and time series cluster analysis to determine the phase, rhythmicity, and unique signature of the transcripts over temporally coordinated expression. Additionally, mass, cell size, histology, and tear secretion of the ELGs were evaluated.

Results

T1DM globally altered the composition of the ELG transcriptome. Specifically, T1DM significantly reprogrammed the circadian transcriptomic profiles of normal ELGs and reorganized core clock machinery. Unique temporal and clustering enrichment pathways were also rewired by T1DM. Finally, normal daily rhythms of mass, cell size, and tear secretion of mouse ELGs were significantly impaired by streptozotocin-induced diabetes.

Conclusions

T1DM significantly reprograms the diurnal oscillations of the lacrimal glands and impairs their structure and tear secretion. This information may reveal potential targets for improving lacrimal gland dysfunction in patients with diabetes.

中文翻译：

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1型糖尿病会损害小鼠眶外泪腺的昼夜振荡。

目的

糖尿病患者有泪腺功能障碍的高风险，但其潜在机制尚不清楚。在这项研究中，我们确定了1型糖尿病（T1DM）如何影响鼠眼眶泪腺（ELG）的昼夜平衡。

方法

通过全身性链脲佐菌素注射在C57BL / 6J小鼠中建立T1DM动物模型。5周后，在24小时的昼夜周期中，每隔3小时收集一次ELG。对提取的总RNA进行高通量RNA测序，并使用Jonckheere-Terpstra-Kendall算法，Kyoto Engenepedia of Genes and Genomes通路分析，相集富集分析和时间序列聚类分析评估节律性转录数据，以确定相，节奏性和转录物在时间协调表达上的独特特征。另外，评估了ELG的质量，细胞大小，组织学和泪液分泌。

结果

T1DM全面改变了ELG转录组的组成。具体来说，T1DM显着地重新编程了正常ELG的生物钟转录组谱，并重组了核心时钟机制。T1DM还重新链接了独特的时间和集群富集途径。最后，链脲佐菌素诱发的糖尿病会严重损害小鼠ELG的正常日常节律，细胞大小和泪液分泌。

结论

T1DM会严重重编程泪腺的昼夜振荡，并损害其结构和泪液分泌。该信息可能揭示改善糖尿病患者泪腺功能障碍的潜在目标。