Mechanistic investigations of diabetic ocular surface diseases

Abstract

With the global prevalence of diabetes mellitus over recent decades, more patients suffered from various diabetic complications, including diabetic ocular surface diseases that may seriously affect the quality of life and even vision sight. The major diabetic ocular surface diseases include diabetic keratopathy and dry eye. Diabetic keratopathy is characterized with the delayed corneal epithelial wound healing, reduced corneal nerve density, decreased corneal sensation and feeling of burning or dryness. Diabetic dry eye is manifested as the reduction of tear secretion accompanied with the ocular discomfort. The early clinical symptoms include dry eye and corneal nerve degeneration, suggesting the early diagnosis should be focused on the examination of confocal microscopy and dry eye symptoms. The pathogenesis of diabetic keratopathy involves the accumulation of advanced glycation end-products, impaired neurotrophic innervations and limbal stem cell function, and dysregulated growth factor signaling, and inflammation alterations. Diabetic dry eye may be associated with the abnormal mitochondrial metabolism of lacrimal gland caused by the overactivation of sympathetic nervous system. Considering the important roles of the dense innervations in the homeostatic maintenance of cornea and lacrimal gland, further studies on the neuroepithelial and neuroimmune interactions will reveal the predominant pathogenic mechanisms and develop the targeting intervention strategies of diabetic ocular surface complications.

Keywords: diabetic keratopathy; dry eye; epitheliopathy; lacrimal gland; neuropathy; pathogenesis.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Zhou, Yang, Wang, Li, Wei and Xie.

Figures

Figure 1

The working model for the low-grade chronic inflammation contributing to diabetic keratopathy. In diabetic mellitus, numerous diabetes-associated danger molecules (such as hyperglycemia, AGEs and NETs), persistently activate NF-κB signaling and NLRP3 inflammasome, resulting in chronic inflammation and pyroptosis, which ultimately postpones corneal epithelial wound healing and impairs re-generation.

Figure 2

SP-NK-1R signaling regulates diabetic corneal epithelial wound healing. (A) In the unwounded corneal epithelium, the elevation of p-Akt, p-EGFR, and Sirt1 level by SP application was attenuated in NK-1 receptor antagonist L-733,060-injected SP-treated diabetic mice. (B) L-733,060 injection reversed the promotion of SP on diabetic corneal epithelial wound healing. (C) L-733,060 treatment reversed the promotion of SP on p-Akt activation and proliferation in the regenerated corneal epithelium. ns, no significance; *p< 0.05. (ref 126).

Figure 3

CNTF promotes corneal epithelial wound healing in diabetic mice. (A) CNTF is decreased in diabetic corneas both in mRNA and in protein level. (B, C) Subconjunctival injection of 50 ng CNTF significantly promotes the corneal epithelial wound healign in diabetic mice. (D) The expression of ΔNp63 and Ki-67 in the regenerating corneal epithelium is upregulated after CNTF treatment. (E) CNTF activated Stat3 signaling in diabetic wounded corneas. "*p< 0.05. (ref 215).

Figure 4

Proposed mechanism of endothelium dysfunction in the diabetic cornea. Endothelial cells from diabetic mice exhibit high levels of ER stress and ER stress appears before morphological changes of the endothelium. Activation of ER stress can promote corneal endothelial dysfunction by triggering mitochondrial dysfunction. Acute injuries, such as glaucoma, can lead to corneal edema and endothelial cell loss.

Figure 5

Mitochondrial dysfunction in diabetic lacrimal gland. Lacrimal gland cells from the diabetic mice after 16 weeks were evaluated with the seahorse XFp analyzer (ref. 267).