Revealing the Angiopathy of Lacrimal Gland Lesion in Type 2 Diabetes

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.

Topical naltrexone increases aquaporin 5 production in the lacrimal gland and restores tear production in diabetic rats

“…Our results support previous studies showcasing atrophied acini in the diabetic lacrimal gland that may reflect decreased cell size and/or secretory function [ 24 , 31 ]. Studies have shown that diabetic rats have smaller secretory vesicles, decreased levels of cations, and decreased total protein [ 24 , 32 ].…”

Electroacupuncture modulates the TLR4-NF-κB inflammatory signaling pathway to attenuate ocular surface inflammation in dry eyes of type 2 diabetic rats

“…However, excessive or chronic inflammation can damage ocular surface tissues and decrease tear film stability, e.g. corneal epithelial defects, decreased corneal nerves [3] decreased conjunctival cuprocytes [4], and atrophy of lacrimal gland alveoli [5]. Numerous prospective and retrospective cohort studies have highlighted the relationship between pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6, etc.)…”

“…T2DM DE is closely related to inflammation [2]. Inflammation on the ocular surface of DE patients with T2DM will lead to destruction of corneal epithelial barrier, nerve damage [3], apoptosis of conjunctival goblet cells [4], and atrophy of lacrimal gland acinifphys [5] causing discomfort symptoms such as dryness, burning sensation, foreign body sensation in the patient's eyes, and even leading to visual dysfunction [6], seriously affecting the life quality of patients..Currently, the eye drops commonly used clinically for T2DM DE include artificial tears and steroid drops [7]. Artificial tears do not have a direct anti-inflammatory effect, treating the symptoms but not the root cause; steroid hormone eye drops will produce increased intraocular pressure, cataracts and other adverse reactions after long-term use [8].Therefore, effective and safe treatment strategies need to be explored for T2DM…”

Atopic dermatitis-associated genetic variants regulate LOC100294145 expression implicating interleukin-27 production and type 1 interferon signaling

“… 22 The Molecular Complex Detection (MCODE) plugin in Cytoscape was then used to cluster the protein interactions in the network using a node score cutoff of 0.2, a module score of >4, a degree cutoff of 2 and a maximum depth of 100. 23 , 24 , 25 , 26 , 27 Next, the Cytohubba plug-in in Cytoscape was used to identify biologically important hub genes that are highly connected via protein-protein interactions as documented in the supplementary text. 28 , 29 …”