Revealing the Angiopathy of Lacrimal Gland Lesion in Type 2 Diabetes

Junfa Xue,Min Ding,Qingjun Zhou,Yanling Dong,Huifeng Wang,Bin Zhang,Shengqian Dou,Lixin Xie,Dongfang Li,Mingming Zhou

doi:10.3389/fphys.2021.731234

Abstract

For a better understanding of diabetic angiopathy (DA), the potential biomarkers in lacrimal DA and its potential mechanism, we evaluated the morphological and hemodynamic alterations of lacrimal glands (LGs) in patients with type 2 diabetes and healthy counterparts by color Doppler flow imaging (CDFI). We further established a type 2 diabetic mice model and performed hematoxylin-eosin (HE) staining, immunofluorescence staining of CD31, RNA-sequencing analysis, and connectivity map (CMap) analysis. We found atrophy and ischemia in patients with type 2 diabetes and mice models. Furthermore, we identified 846 differentially expressed genes (DEGs) between type 2 diabetes mellitus (T2DM) and vehicle mice by RNA-seq. The gene ontology (GO) analysis indicated significant enrichment of immune system process, regulation of blood circulation, apoptotic, regulation of secretion, regulation of blood vessel diameter, and so on. The molecular complex detection (MCODE) showed 17 genes were involved in the most significant module, and 6/17 genes were involved in vascular disorders. CytoHubba revealed the top 10 hub genes of DEGs, and four hub genes (App, F5, Fgg, and Gas6) related to vascular regulation were identified repeatedly by MCODE and cytoHubba. GeneMANIA analysis demonstrated functions of the four hub genes above and their associated molecules were primarily related to the regulation of circulation and coagulation. CMap analysis found several small molecular compounds to reverse the altered DEGs, including disulfiram, bumetanide, genistein, and so on. Our outputs could empower the novel potential targets to treat lacrimal angiopathy, diabetes dry eye, and other diabetes-related diseases.

Highlights

Type 2 diabetes mellitus (T2DM) and diabetic complications have been with high mortality and morbidity year by year and arouse great concern throughout the globe (Vujkovic et al, 2020)
By using gene ontology (GO) analysis, protein-protein interaction (PPI) network, molecular complex detection (MCODE), cytoHubba, and geneMANIA, we aim to identify the hub biomarkers and their related mechanisms in diabetic lacrimal angiopathy
To know the morphological and hemodynamic alterations of lacrimal glands (LGs) from patients with type 2 diabetes, the color Doppler flow imaging (CDFI) was performed for its advantage of demonstrating the shape of LGs and providing real-time dynamic data of blood flow in LGs (Bilgili et al, 2005)

Summary

Introduction

Type 2 diabetes mellitus (T2DM) and diabetic complications have been with high mortality and morbidity year by year and arouse great concern throughout the globe (Vujkovic et al, 2020). Angiopathy in T2DM Lacrimal Lesion of lesion and secretion deficiency in patients affected by diabetes (Jiao et al, 2020; Qu et al, 2021). Previous studies have revealed the LG atrophied and morphology change in type 1 diabetes (Jiao et al, 2020; Qu et al, 2021). Type 2 diabetes accounts for 90–95% of all diabetes morbidity (Basterra-Gortari et al, 2019), the lacrimal lesion of which has not been fully elucidated. The microvascular complication of diabetes generated in retina, kidney, and nervous system (Knudsen et al, 2019) has not been clearly illustrated in the LG

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