Type 1 diabetes mellitus impairs diurnal oscillations in murine extraorbital lacrimal glands

Abstract

PurposePeople 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). MethodsA 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. ResultsT1DM 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. ConclusionsT1DM 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.