|Ahead of print publication
Dry eye disease in patients with diabetes mellitus: An overview
Department of Ocular Inflammation and Immunology, Singapore National Eye Centre; Department of Ocular Inflammation & Immunology, Singapore Eye Research Institute, Singapore
|Date of Submission||29-Jul-2020|
|Date of Decision||21-Aug-2020|
|Date of Acceptance||30-Sep-2020|
Department of Ocular Inflammation and Immunology, Singapore National Eye Centre; Department of Ocular Inflammation & Immunology, Singapore Eye Research Institute
Source of Support: None, Conflict of Interest: None
Dry eye disease (DED) is a global public health issue with significant socioeconomic implications, such as increased health-care costs and negative impact on quality of life., Diabetes mellitus (DM) has been identified as an important systemic risk factor of DED, with a reported prevalence of 20.6%–54.3% worldwide.,,, Poor glycemic control, long duration of diabetes, diabetic peripheral neuropathy (DPN), and diabetic retinopathy (DR) have been reported as risk factors for DED.,,
The secretion and stability of the tear film are diminished in patients with DM compared to age- and gender-matched controls.,,, Chronic hyperglycemia can lead to formation and accumulation of advanced glycation end products, which promote inflammation and oxidative stress contributing to structural damage and dysfunction of the lacrimal gland. Impaired lacrimal innervation due to diabetic autonomic neuropathy may further contribute to diminished tear production in these patients. DPN can lead to decreased corneal nerve fiber density and impaired corneal sensitivity, resulting in decreased reflex tearing., In addition, reduced blinking increases the evaporation of tears., Recent studies show that insulin resistance or deficiency and chronic hyperglycemia can cause loss of Meibomian gland More Details epithelial cells and goblet cells, resulting in an altered tear film., Increased tear evaporation and decreased tear production can result in increased tear osmolarity, activating a series of inflammatory responses. Inflammatory cytokines, such as tumor necrosis factor-alpha and matrix metalloproteinase (MMP)-9, have been implicated in the pathogenesis of DED.
Chronic tear secretion deficiency, DPN, and hyperglycemia can cause corneal epitheliopathy.,, The concentration of lactoferrin and tear-specific prealbumin is decreased in patients with DM. Superficial punctate keratitis, recurrent corneal erosions, persistent epithelial defects, neurotrophic keratopathy, delayed wound healing, and alterations in tear proteins increase the risk of developing microbial keratitis in these patients. Therefore, early diagnosis and intervention of diabetic-associated DED is important to prevent long-term complications.
Clinicians should be aware that patients with DM-associated DED can be asymptomatic due to corneal hypoesthesia caused by chronic hyperglycemia, despite having severe DED. Therefore, it is important to examine the ocular surface and tear film of these patients in addition to DR assessment during routine checkups as emphasized by the authors.
Currently, there are no specific guidelines on treatment of DM-associated DED. Systemic glycemic control and local therapy with topical preservative-free artificial tears, topical antibiotics, autologous serum, bandage contact lenses, amniotic membrane transplantation, and tarsorrhaphy remain the mainstay of treatment of DM-associated DED and persistent epitheliopathy. Topical steroids, cyclosporine eye drops, and bandage/scleral contact lenses should be used with caution in patients with poor glycemic control due to increased risk of infection. Prolonged use of topical nonsteroidal anti-inflammatory eye drops may lead to corneal epithelial breakdown, corneal erosion, ulceration, and perforation. Recent preclinical and clinical studies have shown that growth factors and cytokines significantly enhance corneal re-epithelialization and reverse corneal nerve degeneration in diabetics.,, Topical administration of thymosin beta-4, insulin, naltrexone (opioid antagonist), nicergoline (ergoline derivative), substance P (11-amino-acid polypeptide), aldose reductase inhibitors (ARIs) such as sorbinil and CT-112, and epalrestat (an ARI)-loaded silicone hydrogel contact lenses was effective in treating diabetic keratopathy.,, Oral administration of enalapril, ilepatril, and resolvin-D1was reported to reverse diabetic corneal neuropathy. The limbal epithelial stem cells in diabetic corneas appear to be dysfunctional due to reduced expression of putative markers. Emerging therapies such as adenoviral gene therapy inducing overexpression of c-Met proto-oncogene and/or silencing MMP-10 and cathepsin F genes and inhibition of microRNA-146a using antagomir have been shown to normalize epithelial wound healing and stem cell marker expression in human organ-cultured diabetic corneas. Further research is needed to evaluate the efficacy and safety of these novel therapies, which can potentially halt or reverse the progression of the disease.
| References|| |
Tong L, Waduthantri S, Wong TY, Saw SM, Wang JJ, Rosman M, et al
. Impact of symptomatic dry eye on vision-related daily activities: The Singapore Malay Eye Study. Eye (Lond) 2010;24:1486-91.
Waduthantri S, Yong SS, Tan CH, Shen L, Lee MX, Nagarajan S, et al
. Cost of dry eye treatment in an Asian clinic setting. PLoS One 2012;7:e37711.
Kaiserman I, Kaiserman N, Nakar S, Vinker S. Dry eye in diabetic patients. Am J Ophthalmol 2005;139:498-503.
Yoon KC, Im SK, Seo MS. Changes of tear film and ocular surface in diabetes mellitus. Korean J Ophthalmol 2004;18:168-74.
Yu L, Chen X, Qin G, Xie H, Lv P. Tear film function in type 2 diabetic patients with retinopathy. Ophthalmologica 2008;222:284-91.
Alves M, Calegari VC, Cunha DA, Saad MJ, Velloso LA, Rocha EM. Increased expression of advanced glycation end-products and their receptor, and activation of nuclear factor kappa-B in lacrimal glands of diabetic rats. Diabetologia 2005;48:2675-81.
Misra SL, Craig JP, Patel DV, McGhee CN, Pradhan M, Ellyett K, et al
. In vivo
confocal microscopy of corneal nerves: An ocular biomarker for peripheral and cardiac autonomic neuropathy in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci 2015;56:5060-5.
Guney F, Demir O, Gonen MS. Blink reflex alterations in diabetic patients with or without polyneuropathy. J Neurosci 2008;118:1287-98.
Sagdik HM, Ugurbas SH, Can M, Tetikoglu M, Ugurbas E, Ugurbas SC, et al
. Tear film osmolarity in patients with diabetes mellitus. Ophthalmic Res 2013;50:1-5.
Li DQ, Luo L, Chen Z, Kim HS, Song XJ, Pflugfelder SC. JNK and ERK MAP kinases mediate induction of IL-1beta, TNF-alpha and IL-8 following hyperosmolar stress in human limbal epithelial cells. Exp Eye Res 2006;82:588-96.
Singh R. Managing Diabetic Eye Disease in Clinical Practice. Switzerland: Springer; 2015. p. 72-8.
Fai S, Ahem A, Mustapha M, Mohd Noh UK, Bastion MC. Randomized controlled trial of topical insulin for healing corneal epithelial defects induced during vitreoretinal surgery in diabetics. Asia Pac J Ophthalmol (Phila) 2017;6:418-24.
Yang L, Di G, Qi X, Qu M, Wang Y, Duan H, et al
. Substance P promotes diabetic corneal epithelial wound healing through molecular mechanisms mediated via the neurokinin-1 receptor. Diabetes 2014;63:4262-74.
Alvarez-Rivera F, Concheiro A, Alvarez-Lorenzo C. Epalrestat-loaded silicone hydrogels as contact lenses to address diabetic-eye complications. Eur J Pharm Biopharm 2018;122:126-36.
Davidson EP, Coppey LJ, Shevalye H, Obrosov A, Kardon RH, Yorek MA. Impaired corneal sensation and nerve loss in a type 2 rat model of chronic diabetes is reversible with combination therapy of menhaden oil, α-lipoic acid, and enalapril. Cornea 2017;36:725-31.
Saghizadeh M, Dib CM, Brunken WJ, Ljubimov AV. Normalization of wound healing and stem cell marker patterns in organ-cultured human diabetic corneas by gene therapy of limbal cells. Exp Eye Res 2014;129:66-73.