Diabetic Corneal Neuropathy: Pathogenic Mechanisms and Therapeutic Strategies

Zhou, Ting; Lee, Allie; Lo, Amy Cheuk Yin; Kwok, Jeremy Sze Wai John

doi:10.3389/fphar.2022.816062

Cited by 22 publications

(21 citation statements)

References 169 publications

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“…Recently, DM has reached epidemic proportions and is currently the leading cause of new blindness in adults [ 2 , 24 , 34 , 40 – 43 ]. The human cornea is significantly affected by DM, a disease known as diabetic keratopathy/neuropathy, with complications observed in 45-70% of the diabetic population [ 40 , 42 , 44 , 45 ]. Unfortunately, despite extensive research, the pathobiology and molecular mechanisms are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Monocarboxylate Transporters: Role and Regulation in Corneal Diabetes

Shrestha

Whelchel

Nicholas

et al. 2022

Analytical Cellular Pathology

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Diabetes mellitus (DM) is a group of metabolic diseases that is known to cause structural and functional ocular complications. In the human cornea, DM-related complications affect the epithelium, stroma, and nerves. Monocarboxylate transporters (MCTs) are a family of proton-linked plasma membrane transporters that carry monocarboxylates across plasma membranes. In the context of corneal health and disease, their role, presence, and function are largely undetermined and solely focused on the most common MCT isoforms, 1 through 4. In this study, we investigated the regulation of MCT1, 2, 4, 5, 8, and 10, in corneal DM, using established 3D self-assembled extracellular matrix (ECM) in vitro models. Primary stromal corneal fibroblasts were isolated from healthy (HCFs), type I (T1DMs), and type II (T2DMs) DM donors. Monoculture 3D constructs were created by stimulating stromal cells on transwells with stable vitamin C for two or four weeks. Coculture 3D constructs were created by adding SH-SY5Y neurons at two different densities, 12 k and 500 k, on top of the monocultures. Our data showed significant upregulation of MCT1 at 4 weeks for HCF, T1DM, and T2DM monocultures, as well as the 500 k nerve cocultures. MCT8 was significantly upregulated in HCF and T1DM monocultures and all of the 500 k nerve cocultures. Further, MCT10 was only expressed at 4 weeks for all cocultures and was limited to HCFs and T1DMs in monocultures. Immunofluorescence analysis showed cytoplasmic MCT expression for all cell types and significant downregulation of both MCT2 and MCT4 in HCFs, when compared to T1DMs and T2DMs. Herein, we reveal the existence and modulation of MCTs in the human diabetic cornea in vitro. Changes appeared dependent on neuronal density, suggesting that MCTs are very likely critical to the neuronal defects observed in diabetic keratopathy/neuropathy. Further studies are warranted in order to fully delineate the role of MCTs in corneal diabetes.

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Section: Discussionmentioning

confidence: 99%

Monocarboxylate Transporters: Role and Regulation in Corneal Diabetes

Shrestha

Whelchel

Nicholas

et al. 2022

Analytical Cellular Pathology

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“…Table 5 and Figure S1B list the top 25 tear proteins that are significantly up-and down-regulated after treatment. Upon GSEA analysis, we found that three neuronal regulation-related pathways were significantly upregulated after treatment: (1) MAPK signaling pathway (ES:0.53; p=0.009), (2) neurotrophin signaling pathway (ES:0.59; p=0.01), and (3) linoleic acid (LA) metabolism (ES:1.00; p=0.01) (Table 6). Ribosome family was significantly downregulated (ES:-0.67; p=0.002).…”

Section: Tear Proteomic Profiles and Pathway Enrichment Analysismentioning

confidence: 99%

“…Diabetic neuropathy is one of the most common microvascular complications of uncontrolled diabetes mellitus (DM) (1). Chronic hyperglycaemia results in the accumulation of advanced glycation end products (AGE), and the production of reactive oxygen species (ROS), both of which increases oxidative stress and inflammation to pericytes and endothelium of capillaries, thereby reducing microvascular supply to Schwan cells or neurons (2). Prolonged hyperglycaemia also inhibits nerve growth factor (NGF) for neuronal health and myelin formation, leading to reduced nerve velocity (3).…”

mentioning

confidence: 99%

Oral Peroxisome Proliferator-Activated Receptor-Alpha (PPAR)-α Agonist Enhances Corneal Nerve Regeneration in Patients with Type II Diabetes Mellitus

Teo¹,

Lin²,

Lee³

et al. 2022

Preprint

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<p>Diabetic corneal neuropathy (DCN) is a common complication of diabetes mellitus (DM). However, there are very limited therapeutic options. We investigated the effects of a peroxisome proliferator-activated receptor-alpha (PPAR)-α agonist, fenofibrate, on thirty patients (60 eyes) with type II DM. On in-vivo confocal microscopy evaluation, there was significant stimulation of corneal nerve regeneration and a reduction in nerve edema after 30 days of oral fenofibrate treatment, evidenced by the significant improvement in corneal nerve fiber density (CNFD) and corneal nerve fiber width, respectively. Corneal epithelial cells morphology also significantly improved in its cell circularity. Upon clinical examination, fenofibrate significantly improved patients’ neuropathic ocular surface status by increasing tear break-up time along with a reduction of corneal and conjunctival punctate keratopathy. Tear substance P (SP) concentrations significantly increased after treatment, suggesting an amelioration of ocular surface neuroinflammation. The changes in tear SP concentrations was also significantly associated with the improvement in CNFD. Quantitative proteomic analysis demonstrated that fenofibrate significantly upregulated and modulated the neurotrophin signalling pathway, linolenic acid, cholesterol and fat metabolism. Complement cascades, neutrophil reactions, and platelet activation were also significantly suppressed. Our results showed that fenofibrate could potentially be a novel treatment for patients with DCN.</p>

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“…Continuous hyperglycaemic can destroy nerve structures, decrease nerve density,6 decrease corneal perception and sensitivity7 and reduce tear secretion. More specifically, impaired regulation of the ocular nerve decreases nerve conduction velocity, which reduces the number of blinks and increases tear evaporation,8 thereby promoting dry eye. Moreover, when in a state of persistent hyperglycaemic, the tear osmotic pressure increases, while the conjunctival mucin secretion is significantly reduced, leading to decreased tear secretion and increased instability of the tear film,9 10 all of which induce dry eye.…”

Section: Introductionmentioning

confidence: 99%

Acupuncture for patients with type 2 diabetes mellitus with dry eye: protocol for a systematic review and meta-analysis

Wei

et al. 2022

BMJ Open

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IntroductionThe global incidence of patients with type 2 diabetes mellitus (T2DM) with dry eye is increasing annually, which imposes additional healthcare costs and financial burden on families and societies. In clinical practice, artificial tears are often used for symptomatic treatment, but these can only relieve the symptoms of discomfort. Acupuncture is a widely used alternative therapy. Indeed, randomised trials have found that acupuncture confers a definite therapeutic effect on patients with T2DM with dry eye. However, systematic reviews on the effectiveness and safety of acupuncture are lacking, therefore this systematic review aims to evaluate the effectiveness and safety of acupuncture for T2DM with dry eye.Methods and analysisFour English databases (PubMed, Cochrane Library, Embase and Ovid), three Chinese databases (China National Knowledge Infrastructure, Wanfang, Chonqing VIP Information), three Japanese databases (Japan Science, Technology Agency and Japan Medical Abstracts Society) and three Korean databases (Korean Medical database, Oriental Medicine Advanced Searching Integrated System and Research Information Service System) will be searched for reports published between 1 January 2007 and 1 October 2021. Only randomised controlled trials will be included, and language or publication dates will not be restricted. Two researchers will independently extract, manage and analyse data. The primary outcomes will include Schirmer’s I test, breakup time, corneal fluorescein staining and ocular surface disease index scores. Secondary results will include visual analogue scale scores for ocular symptoms and any adverse events related to acupuncture. We will use Review Manager V.5.4 for the meta-analysis. The risk of bias will be independently assessed using Cochrane’s ‘risk of bias’ tool.Ethics and disseminationEthical approval will not be required since raw data will not be collected or generated. Our findings will be disseminated through peer-reviewed journal.PROSPERO registration numberCRD42021271891.

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Diabetic Corneal Neuropathy: Pathogenic Mechanisms and Therapeutic Strategies

Cited by 22 publications

References 169 publications

Monocarboxylate Transporters: Role and Regulation in Corneal Diabetes

Monocarboxylate Transporters: Role and Regulation in Corneal Diabetes

Oral Peroxisome Proliferator-Activated Receptor-Alpha (PPAR)-α Agonist Enhances Corneal Nerve Regeneration in Patients with Type II Diabetes Mellitus

Acupuncture for patients with type 2 diabetes mellitus with dry eye: protocol for a systematic review and meta-analysis

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