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A systematic review on the impact of diabetes mellitus on the ocular surface

A systematic review on the impact of diabetes mellitus on the ocular surface OPEN Citation: Nutrition & Diabetes (2017) 7, e251; doi:10.1038/nutd.2017.4 www.nature.com/nutd REVIEW A systematic review on the impact of diabetes mellitus on the ocular surface 1,2 2,3,4 5,6,7,8 K Co Shih , KS-L Lam and L Tong Diabetes mellitus is associated with extensive morbidity and mortality in any human community. It is well understood that the burden of diabetes is attributed to chronic progressive damage in major end-organs, but it is underappreciated that the most superficial and transparent organ affected by diabetes is the cornea. Different corneal components (epithelium, nerves, immune cells and endothelium) underpin specific systemic complications of diabetes. Just as diabetic retinopathy is a marker of more generalized microvascular disease, corneal nerve changes can predict peripheral and autonomic neuropathy, providing a window of opportunity for early treatment. In addition, alterations of immune cells in corneas suggest an inflammatory component in diabetic complications. Furthermore, impaired corneal epithelial wound healing may also imply more widespread disease. The non- invasiveness and improvement in imaging technology facilitates the emergence of new screening tools. Systemic control of diabetes can improve ocular surface health, possibly aided by anti-inflammatory and vasoprotective agents. Nutrition & Diabetes (2017) 7, e251; doi:10.1038/nutd.2017.4; published online 20 March 2017 INTRODUCTION reviews) and 110 relevant original articles. For example, articles that involved only the posterior segment of the eye (retina, Diabetes mellitus (DM) is a significant public health problem. It is vitreous) or involving only ‘diabetes insipidus’ and not ‘diabetes estimated that more than 342 million people worldwide will suffer mellitus’ would be considered irrelevant. A total of 106 were from DM by 2030 and the total health burden incurred by DM will deemed irrelevant. be driven by the severity of diabetic complications in different organs. The ocular surface, including the superficial and transpar- ent cornea, is known to be involved in diabetes in various ways: CORNEA EPITHELIAL DISEASE AND OCULAR SURFACE this includes common diseases like dry eye and recurrent corneal 1 ABNORMALITIES erosions, previously reviewed elsewhere. However, new research It is known that diabetes is associated with impaired wound beyond 2008 has not been systematically reviewed, even after the 2–19 healing. This is evident in the corneal epithelium. Diabetic eyes are emergence of fairly recent review articles. This is an important at increased risk of dry eye, superficial punctate keratitis, recurrent issue to address as new developments such as cellular, molecular 20,21 corneal erosion syndrome and persistent epithelial defects. As biology and animal genetics have advanced considerably in the the corneal epithelium is the first layer of the eye, it is constantly last few years. Here, we provide a systematic review of the recent subjected to wear and tear and it needs to be constantly literature (published 2009–2015), which enlightens on the role of regenerated. Any process that affects wound healing or the speed the ocular surface and cornea in DM (Figure 1) and research on of epithelial regeneration will have physiological impact and potential treatment strategies. 22–25 increases morbidity including ocular pain and redness. Recently a human study conducted in a hospital showed for the first time that tear levels of type 1 and 2 diabetic individuals had MATERIALS AND METHODS significantly higher insulin-like growth factor binding protein A literature search was conducted on the 5th of January 2016 in (IGFBP3) compared with age-matched normal adults. IGFBP3 is a the NCBI Entrez Pubmed database and included search terms multifunctional protein that is known to play a negative regulatory diabetes and cornea. Articles were limited to journal articles in role in IGF signaling by binding and sequestrating it, competing which the keywords ‘cornea’ or ‘conjunctiva’ occur in conjunction with its cellular receptor IGFR-1. In the wider context, IGFBP3 has with the keyword ‘diabetes’ in the textword (tw) field of the been known to regulate insulin resistance, apoptosis as well as search. We only examined journal articles published between 1st oxidative damage. The processes regulating the secretion of of January 2009 and 31st of December 2016. The 234 articles IGFBP3 from corneal epithelial tissue is not known, but in identified were then curated by two coauthors (KS and LT) for experiments with immortalized human corneal epithelial cells, it relevance, via abstract or the full text of the article, and this was found that high levels of glucose in the culture medium can produced a list of 23 review articles, letters or commentaries (18 induce the production of IGFBP3, suggesting that the 1 2 Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Research Center of Heart, Brain, Hormone and Healthy 3 4 Aging, The University of Hong Kong, Hong Kong; Department of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Pharmaceutical Biotechnology, 5 6 The University of Hong Kong, Hong Kong; Singapore Eye Research Institute, National Eye Centre, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, 7 8 Singapore; Department of Ophthalmology, Singapore National Eye Center, Singapore and Department of Ophthalmology, Duke-NUS Medical School, Singapore. Correspondence: Dr L Tong, Department of Ophthalmology, Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751, Singapore. E-mail: [email protected] Received 5 October 2016; revised 10 November 2016; accepted 14 November 2016 Systemic review diabetes ocular surface KCo Shih et al Figure 1. Schematic showing pathogenesis of corneal disease in diabetes mellitus. Hyperglycemia and formation of advanced glycation end products have distinct effects on different parts of the cornea, resulting in three principal types of tissue dysfunction with physiological effects that can be measured. (1) Defective wound healing in the corneal epithelium, (2) abnormalities of sub-basal nerves and (3) loss of corneal endothelial pump function. (1) Raised blood glucose promotes IGFBP3 release, which in turn competitively inhibits IGF-1, whereas TGFb3, EGFR, CNTF are suppressed in hyperglycemic states. The consequential reduction in epithelial cell proliferation and increased apoptosis impacts on epithelial wound healing. (2) Neuronal damage is a key defect in diabetes mellitus. Prolonged hyperglycemia results in the accumulation of advanced glycation end products which promotes inflammation and oxidative stress. NGF and sphingolipids are key to neuronal health and myelin formation, but their production are inhibited in hyperglycemic states. (3) Prolonged hyperglycemia also results in endothelial cell loss and impairment in pump function. Apart from these processes, the swelling of the corneal stroma (the main bulk of the cornea) may be due to loss of epithelial barrier, crosslinking of stromal collagen and matrix, and loss of the endothelial pump. CNTF, ciliary neurotrophic factor; EGFR, epithelial growth factor receptor; IGF-1, insulin-like growth factor 1; NF-kB, nuclear factor kappa-light-chain- enhancer of activated B cells transcription factor; NGF, nerve growth factor; TGFb3, transforming growth factor beta-3. Solid blue arrows— activation/promotion, red stop arrows—inhibition or negative regulation. hyperglycemia in patients may be the cause of the IGFBP3 Use of diabetic animals has both advantages and constraints. upregulation. This paper did not examine other potential sources The obvious advantage is the ability to obtain ocular tissue, but of IGFBP3 such as lacrimal glands and immune cells. In addition, the main advantage of using these models is the possibility of the clinical examination results of the corneal epithelium of the examining changes before and after induction of diabetes. Such changes are almost impossible to evaluate in human patients as participants such as presence of epitheliopathy were not they would not have come to the attention of health professionals reported. 27,28 prior to the development of diabetes. The major limitation of Two studies with C57 db/db mice and four studies involving 24,29–31 animal models is that the induction of DM occurs fairly rapidly rats showed that hyperglycemia induced detrimental using one intervention compared with the more chronic, multi- effects on the cornea epithelium-basement membrane complex. factorial DM in humans, and therefore the disturbance may not be In these studies, decreases in corneal epithelial function were translatable to human disease. Induction of diabetes may be via documented by an increase in corneal thickness, and structural 24,29,30 injection of streptozotocin in Sprague Dawley (SD) rats, or in some changes were examined by electron microscopy. Since the cases, rats may be naturally diabetic such as Otsuka Long-Evans normal corneal epithelium plays an important barrier function Tokushima fatty (OLETF) rats. Streptozotocin destroys beta islet in excluding water from entering the stroma, a reduction in cells in the pancreas of the animals, with reduction of insulin the barrier function will manifest as edema and swelling secretion and consequent hyperglycemia. The hyperglycemia- of the normally relatively dehydrated stroma. The component of related effects as well as the oxidative stress associated with the epithelium forming the barrier is largely sub-served by tight ingestion of fat and ethanol in OLEFT rats then induce systemic junctional complexes between cornea epithelial cells, visualized as organ damage. electron dense structures. Loss or disruption of these tight One of the molecular changes detected in animal eyes is the junction structures or loss of basal corneal epithelial cells on measurement of levels of advanced glycation end products imaging would explain loss of epithelial function. The loss of (AGE). This is an important pathological outcome as it is epithelial function can affect vision because the onset of edema considered to be the mediator for all chronic DM complications causes cornea opacification and will directly affect transmission of including macrovascular and microvascular complications such as light through the cornea. diabetic retinopathy in the eye. The accumulation of AGE in the Nutrition & Diabetes (2017) 1 – 10 Systemic review diabetes ocular surface KCo Shih et al cornea epithelium-basement membrane shifts local cell signaling Specific nerve indices may have been found to be useful in a towards pro-apoptotic and antiproliferative pathways, as well as particular region of the cornea for some clinical scenarios. Analysis 44–49 increases oxidative stress and inflammation. A typical way of of the sub-basal nerve plexus can be performed in two regions of the cornea: central cornea and the inferior whorl. For measuring oxidative stress in the ocular surface tissue is the example, it has also been reported that the nerve fiber density at quantification of the level of the oxidized nucleotide 8- the inferior whorl region is more sensitive to early nerve fiber hydroxydeoxyguanosine. A separate study found the gamma- damage than the central corneal region, in DM patients before glutamyl transferase level in the tear to be reduced in 14 type 1 development of peripheral neuropathy. and 2 DM participants compared with 14 control participants. Scans can be evaluated manually (CCModule), in semiauto- However, in cornea buttons of cadavers, the tissue levels of the mated fashion (NeuronJ) or in a fully automated (ACCModule) enzyme were lower in type 1 DM than in type 2 DM and controls. 52,53 technique. All three methods were reported to have high While these are interesting results in view of the possible role of repeatability, which can be further improved with experience but the transferase in oxidative stress, more studies are required to 54–60 33 not by increasing magnification. The speed of image analysis determine the mechanistic significance. can be improved with use of automated quantification techniques As DM is a chronic disease, it is important to differentiate 13,61,62 as well as wide-field imaging. Calculations from full molecular changes that induce the disease as opposed to automation are well correlated to those by manual methods, molecules that mediate secondary complications. Distinct ultra- and so may be useful in communities without a manual structural tissue alterations may occur in pre-diabetic eyes as well evaluator. 29 23,28 as in established DM. Here in vitro studies and animal models are useful to chart the temporal changes as the corneal Clinical studies levels of epithelial growth factor receptor, ciliary neurotrophic factor and nuclear factor kappa B may be determined at different It is well known for many years that corneal nerve density is reduced in type 1 DM. Recently both types of DM have been stages of disease. TGFb3, epithelial growth factor receptor and associated with reduction of corneal nerve density and other ciliary neurotrophic factor have already been found to promote 19,45,47,63–65 corneal nerve abnormalities (Table 1). corneal epithelial wound healing in studies on wound healing and Reduction in corneal nerve fiber density is a characteristic found to be reduced in corneas of diabetic animals. The nuclear manifestation of diabetic corneal neuropathy, with demonstrated factor kappa B on the other hand is an important transcription progression over time, in a 4 year cohort study of DM participants factor that affects inflammation and cell development found to be 34–36 from two countries (Australia and UK). increased in corneas of diabetic animals. An interesting question would be whether good glycemic control restores the corneal nerve innervation and dysfunction? CORNEA NEUROPATHY Two clinical cohort studies have concluded that once DM (type 1 and type 2) was established, good glycemic control was able to The sensory innervation of the cornea is a major determinant of 67,68 improve but not completely reverse corneal neuropathy. epithelial health and healing capacity. This may be mediated by Corneal nerve parameters have been found to correlate to secretion of substance P by the nerves and binding to neurokinin- diabetic peripheral neuropathy and autonomic neuropathy 1 receptor on the epithelial cells. Corneal nerves are branches of 43,46,48,49,66,69–73 (Table 2). Diabetic peripheral neuropathy, a the ophthalmic nerve, which is a branch of the trigeminal cranial common complication in up to 54% of diabetic population, is a nerve. They perforate the corneal stroma at the medial and lateral significant cause of morbidity and poor quality of life in diabetic positions and branch into neurites that eventually sprout nerve 3 patients. As such, early detection of high-risk patients can pre- endings anteriorly into the corneal epithelium. empt the course of the disease with measures such as better foot- The cornea is the most densely innervated structure in humans, care to improve healthcare outcomes. with nerve fibers playing an important neurotrophic role in the Conventional clinical diagnosis of diabetic peripheral neuro- development of a healthy corneal surface. Loss of neurotrophic pathy includes clinical assessment and nerve conduction studies. function may result in a non-healing or persistent cornea epithelial However, these tests detect large fiber deficits, rather than the defect or neurotrophic ulcer. This has associated cornea edema small unmyelinated C and thinly myelinated Aδ-nerve fibers which and disturbance of visual function and is an important cause of 15,74–76 are affected earlier in the course of the disease. The higher morbidity in cornea clinics. density and the preponderance of small nerve fibers in the cornea Unlike other areas of the body, corneal nerves can be easily may explain why corneal nerve fiber changes can be detected visualized in the transparent anterior corneal stroma by modern before awareness of diabetic peripheral neuropathy in the lower imaging techniques in clinical scenarios without invasive biopsy 6,16,17,45,77 limbs. Decreases in nerve fiber length in sub-basal nerve procedures. Essentially the in vivo findings have been confirmed plexus have also been found to be associated with subclinical by cadaveric ex vivo studies. diabetic autonomic neuropathy which may be life-threatening, including cardiovascular complications such as arrhythmias or 46,71,72 Advances in confocal imaging techniques sudden cardiac deaths. The vagal function is used as a measure of autonomic neurological function, assessed by the The most important advance in the last few years is the use of change of heart rate in response to breathing and posture. modern scanning laser ophthalmoscopy. The most common form of this in vivo confocal microscopy is the Heidelberg Retinal Tomography (Heidelberg, Germany), which is performed in Mechanisms of corneal neuropathy 10,11,14,41 conjunction with a corneal modular lens. Images acquired Broadly, peripheral neuropathies are considered microvascular DM are processed by imaging software for indices of nerve fiber complications as a result of nerve ischemia. The conventional view density, nerve fiber length, nerve branch density and nerve is that AGE initiates damage to the pericytes and endothelium of tortuosity in the sub-basal nerve plexus because changes in this capillaries and reduces microvascular supply to Schwann cells or layer are more relevant in DM than in intrastromal nerves. One neurons. This consequently decreases neuronal function. If the research group used NeuronJ, a plug-in for the NIH freeware status of corneal nerves reflects peripheral nerve status, under- 43 3 Image J whereas the other group used proprietary ACModule standing the mechanism of the corneal neuropathy is vital. and CCModule software developed in the University of Microvascular abnormalities occur in the retina as well as in the Manchester. cornea. Reduction of corneal nerve fiber density or length have Nutrition & Diabetes (2017) 1 – 10 Systemic review diabetes ocular surface KCo Shih et al Table 1. Studies comparing corneal nerve parameters in diabetic subtypes a b c Source Country Groups Sample size Method Parameter (mean) Outcomes Associations − 2 Messmer et al. Germany Type I and II 13/54/24 HRT II NFD (no. mm ) DM1/DM2/C: Increasing severity of nerve fiber 45 −2 (2010) DM vs Image J NFL (mm mm ) 16.9/16.1/23.3 parameters with higher stages of −2 controls Esthesiometer NBD (no. mm ) 9.7/10.7/16.1 diabetic retinopathy, history of NT 1.5/1.6/1.4 nephropathy, peripheral neuropathy, and decreased corneal sensation predictive of abnormal CCM parameters, first paper to demonstrate abnormal CCM parameters in patients with normal corneal and vibration sensation −2 Ischibashi et al. Japan Type I DM vs 38/38 HRT III NFD (no. mm ) DM1/C: HbA1c level and blood pressure were 63 −2 (2012) controls Image J NFL (mm mm ) 25.32/36.62 an independent negative predictors of NT 9.80/13.65 NFL and NFD Beading (mm) 3.13/1.74 22.38/30.44 −2 Nitoda et al. Greece Type II DM 46/47/46/47 HRT II, NFD (no. mm ) DM2 noDR/NPDR/ Positive correlation between corneal 47 −2 (2012) (noDR/ MATLAB NBD (no. mm ) PDR/C: neuropathy and peripheral neuropathy −2 NPDR/NPDR/ NFL (mm mm ) 27.4/23.7/18.8/31.3 PDR) vs NT 39.9/30.6/25/45.1 controls 14.8/12.3/10.4/16.6 1.8/1.9/1.9/1.7 −2 Zhivov et al. Germany DM vs 36/20 HRT II NFD (mm mm ) DM/C: No difference in CCM parameters 64 −2 (2013) controls GIMP NFL (mm mm ) 0.006/0.020 between patients with or without −2 Non-invasive NBD (no. mm ) 6.22/19.99 diabetic retinopathy, corneal sensation esthesiometer 25.3/141.9 was significantly lower in the diabetic group than in controls −2 Wang et al. China Type II DM 45/50 — NFL (mm mm ) DM2/C: Pain severity of diabetic peripheral 19 −2 (2014) vs controls NBD (no. mm ) 11/13 neuropathy showed negative NT 47/62 3.2/2.8 correlation with NFL and NBD, positive correlation with NT −2 Ziegler et al. Germany Type II DM 86/48 HRT II NFL (mm mm ) DM2/C: 65 −2 (2014) vs controls — NFD (no. mm ) 19.7/24.9 −2 Esthesiometer NBD (no. mm ) 299.2/397.3 165.2/226.7 a b Abbreviations: DM, diabetes mellitus; DR, diabetic retinopathy; NPDF, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. NBD, nerve branch density; NFD, nerve fiber density; NFL, nerve fiber length; NT, nerve tortuosity. C, control; DM1, type 1 diabetes mellitus; DM2, type 2 diabetes melliltus. been shown to predict the development of diabetic retinopathy as evaluation of corneal sensitivity which is a functional outcome of 45,47,78 well as sight-threatening retinopathy. nerve innervation. These studies, except one, employed Cochrat The formation of AGE may not be the initial trigger for pericyte Bonnet esthesiometry, which may not be as sensitive as a gas or damage or neuronal loss. Inflammation may play a role as high Belmonte esthesiometry. Nevertheless, the studies were able to concentrations of Langerhans cells and dendritic cells, the main find an association between corneal nerve parameters and corneal 6,46,49,75,76,79 antigen-presenting cells in the ocular surface, aggregate around sensitivity. 79,80 corneal nerve fibers early in the disease process. In addition, It is also well known that apart from being neurotrophic, loss of levels of neurotrophic factors may be reduced in DM, for example, corneal sensation also reduced lacrimal tear production since the reduction in serum nerve growth factor and lipids such as corneal receptors are the afferent limb of the lacrimal reflex arc. sphingolipids have been detected in diabetic eyes compared with The reduction of corneal innervation has been linked to abnormal 81,82 controls. tear function as well as more frequent and severe symptoms of 9,21,27,43,83–86 The cause or extent of immune dysfunction, if any, in humans dry eye in DM patients. These studies included those with type 2 DM is not known. It has been found that immune cell with or without previous surgical procedures such as LASIK and infiltration of animal corneas may precede the induced hypergly- cataract surgeries. In one study, abnormal corneal innervation cemia (ARVO 2015 e-abstract 3076). In fact, in a longitudinal rat manifested as tear film dysfunction and debilitating, chronic study, the pre-diabetic obese rats have already manifested a irritation of the eye in type 1 but not in type 2 DM. similar amount of corneal nerve abnormalities with the diabetic rats. This suggests that accumulation of AGE, which is CORNEA STROMA AND BIOMECHANICS dependent on hyperglycemia and not present in pre-diabetic animals, is unlikely to be the cause of immune dysfunction in The corneal structure underneath the epithelium and the these animals. More animal studies with a mechanistic approach Bowman’s layer is called the stroma. The corneal stroma is would be necessary to determine the cause of immune important because it accounts for 90% of the thickness of the dysfunction in DM. cornea and therefore its tensile strength and biomechanical Do changes in corneal nerve structure lead to functional properties in general. The thickness of the human cornea is the alteration? To answer this question the newer studies in Tables 1 most frequently measured parameter in clinical biometry of the and 2 also included corneal esthesiometry. This is a method of eye. The main novelty in the recent clinical papers on corneal Nutrition & Diabetes (2017) 1 – 10 Systemic review diabetes ocular surface KCo Shih et al Table 2. Studies comparing corneal nerve parameters in different stages of diabetic peripheral neuropathy a c Source Country Groups Sample size Method Parameter Outcomes Associations (mean) −2 Edwards et al. UK and Type I DM 143/88/61 HRT III NFL (mm mm ) DM1/C: 18.3/16/20 Baseline findings of longitudinal 69 −2 (2012) Australia (without CCMetrics NBD (no. mm ) 69/58/80 study: NFL and NBD strongly PN/with NT 0.22/0.23/0.21 correlated with nerve DPN) vs conduction study parameters, controls NFL inversely correlated with HbA1c and duration diabetes −2 Petropoulos UK DM (no 50/26/ HRT III NFD (no. mm ) noPN/modPD/sev PN/C: Symmetrical reduction in CCM 48 −2 et al. (2013) PN/mild 17/18/47 CCMetrics NBD (no. mm ) 26.9/23.25/18.9/13.1/36.95 parameters for all groups except −2 PN/mod NFL (mm mm ) 55.5/48.25/32.4/19.6/96.55 those with severe neuropathy PN/sev PN) NT 20.05/17.6/14.7/9.75/27.25 vs controls 18.2/21.2/18.45/16.45/16.4 −2 Pritchard et al. UK and Type I DM 166/76/154 HRT III NFL (mm mm ) DM2/C: 19/13/23 Baseline of longitudinal study, 49 −2 (2014) Australia (without CCMetrics NBD (no. mm ) 60/40/80 reduction in corneal nerve fiber PN/with Esthesiometry length already noted in DM DPN) vs patients without peripheral controls neuropathy, reduction in corneal sensitivity only in type I DM patients with peripheral neuropathy −2 Stem et al. USA DM (no 25/10/8/9 HRT II NFL (mm mm ) noPN/midPN/severe (2014) PN/mild NeuronJ PN/C: 15.1/18.5/12.5/20.7 PN/severe PN) vs controls −2 DeMill et al. USA DM (no or 16/9/9 HRT II NFL (mm mm ) noPN/severe PN/C: 18/12/ Tear osmolarity increases and (2015) mild PN/ NeuronJ 20.5 NFL decreases with increasing severe PN) Esthesiometry severity of PN, DM patients had vs controls lower Schirmer's test values than controls, no differences in OSDI or VFQ-25 scores, TBUT and ocular surface staining between groups −2 Tavakoli et al. UK DM 15/19/18 Confoscan P4 NFD (no. mm ) noAN/AN/C: 35.70/48.26 CCM findings correlated 71 −2 (2015) (without NBD (no. mm ) 21.24/30.09 7.08/9.74 significantly with autonomic −2 AN/with NFL (mm mm ) symptoms (COMPASS and CASS) AN) vs controls Misra et al. New Type I DM 53/40 HRT II Sub-basal nerve DM1/C: 11/21.17 Negative correlation between (2015) Zealand vs controls analySIS 3.1 density corneal sensitivity and −2 Esthesiometry (mm mm ) autonomic nerve function, 50% of patients with abnormal CCM findings had otherwise no evidence of peripheral or autonomic neuropathy −2 Maddaloni Italy Type I DM 36/20 Confoscan 4, NFD (no. mm ) noAN/AN/C: 51.7/32.8/92 CCM findings lower in DM 72 −2 et al. (2015) (without Image J NFL (mm mm ) 1.4/1.9/1.4 patients with autonomic AN/with Beading (mm) 14.8/15.3/20.6 neuropathy than those without AN) vs controls −2 Dehghani Australia Type I DM 147/60 HRT III, NFD (no .mm ) noPN/withPN/C: Baseline (left). Prospective: 66 −2 et al. (2014) (without ACCMetrics NBD (no. mm ) 18.3/16.3/22.3 significant annual reduction in −2 PN/with NFL (mm mm ) 24.2/23.7/35.1 nerve fiber density in PN group PN) vs 16/15/18.1 vs controls (−0.9 per mm per controls year vs − 0.06 per mm per year) CCM findings correlated with peroneal nerve conduction velocity (r= 0.38) and cold sensation threshold (r = 0.40) −2 Chen et al. UK Type I DM 63/26 HRT III NFD (no. mm ) noPN/withPN/C: Comparable diagnostic efficacy 73 −2 (2015) (without CCMetrics NBD (no. mm ) 28.3/16.9/36.8 between confocal microscopy −2 PN/with ACMetrics NFL (mm mm ) 56.1/48.2/56.1 measurements and −2 PN) vs NFD (no. mm ) 20.2/14.8/26.7 intraepidermal nerve fiber −2 controls NBD (no. mm ) 22.6/13.5/31.3 density (via skin biopsy, gold −2 NFL (mm mm ) 26.2/15.4/44.6 standard) 13.4/8.8/17.7 a b Abbreviations: AN, diabetic autonomic neuropathy; DM, diabetes mellitus; PN, diabetic peripheral neuropathy. NBD, nerve branch density; NFD, nerve fiber density; NFL, nerve fiber length; NT, nerve tortuosity. C, control; DM1, type 1 diabetes mellitus; DM2, type 2 diabetes melliltus. Nutrition & Diabetes (2017) 1 – 10 Systemic review diabetes ocular surface KCo Shih et al biomechanics involved the assessment of corneal hysteresis and studies, except for one study comparing endothelial counts 105–112 resistance force, due to the recent availability of the Ocular between diabetic and non-diabetic cadaveric donors. The 84,88,89 Response Analyser, which can quantify these two para- biggest study of the 5, conducted in Vellor, India, involved 153 meters. Hysteresis refers to the amount of force required to indent participants with DM and 163 age-matched controls, and was the cornea as well as the recovery from the indentation. performed on patients before and after cataract surgery up to Resistance force is the hysteresis normalized to the cornea shape. 3 months postoperatively. Preoperative examinations showed A higher hysteresis suggests a more rigid and less deformable no statistically significant difference between the groups in any of cornea. Seven cross-sectional clinic-based studies in Western the corneal endothelial parameters. Both DM and controls had 87,90–92 93 89 88 94 Europe, United States, Brazil, Israel and Iran have decreases in endothelial counts and increase in morphological found type 1 and type 2 DM participants to have higher hysteresis, abnormalities (increase in cell sizes or polymegathism and whereas only one study (Turkish study) found them to have a increased variability of shape called pleomorphism) at 6 weeks lower hysteresis, compared with age-matched controls. In one and 3 months post-operation. The authors reported that in the study, it was found that the fasting blood glucose level was control group the rate of loss of corneal endothelial cells between significantly but weakly correlated (r = 0.28) to the corneal 6 weeks and 3 months was relatively milder compared with the hysteresis. DM group (P = 0.023). However, the actual measurements were Two other studies published in this recent period on corneal not significantly different at any time points, suggesting that none morphology found DM to be associated with a greater corneal of the differences discovered were clinically relevant. It is worth 96–98 thickness, which was consistent with reports earlier than noting that this Indian study evaluated only small incision manual 2008. It is noteworthy that patients with proliferative, non- cataract surgery but did not investigate phacoemulsification; the proliferative retinopathies and those with no diabetic retinopa- latter is the more common form of surgery in the developed world thies did not have significantly different corneal and potentially induces more corneal endothelial cell loss than 90,97–100 113 thicknesses. In addition, a study in 100 children aged 6– manual surgery. 17 years with type 1 DM in Romania had an increase in corneal The other five papers were cross-sectional studies conducted in 105–109 thickness compared with an equivalent number of children of the Korea, Malaysia and Hungary, Poland and Denmark. These 101 96 same age, and similar findings had been reported in Turkey. studies excluded participants with prior cataract surgery or history The reason why DM is associated with greater corneal hysteresis of ocular disease, and reported statistically significant association or thicknesses is not completely known, apart from the relation- of type 2 DM with increased clinical features of corneal endothelial ship between increased corneal thicknesses in cases of overt dysfunction (reduced endothelial count, and polymegathism and corneal epitheliopathy. However, it has been speculated that the pleomorphism). Nevertheless, the magnitude of the reported accumulation of AGE in the cornea stroma of diabetics may occur differences between the DM and age-matched controls in these together with non-enzymatic crosslinking between collagen studies was very small. For example, in the Malaysian study, the molecules and proteoglycans. The crosslinking would theoretically mean corneal endothelial counts was 2541 cells per mm in DM explain stiffening and thickening of the cornea. One study compared with 2660 cells per mm in controls, with a difference of compared eight monkeys with insulin-dependent diabetes about 120 cells per mm . By excluding participants with (streptozotocin injection) to four controls. In the diabetic eyes ophthalmic problems, these studies would have included only crosslinking has manifested ultra-structurally as abnormal collagen participants with shorter duration of DM. Had these studies fibril aggregates in the stromal matrix on transmission electron recruited DM participants with longer durations, it may be microscopy. This is consistent with published evidence possible to discover greater magnitudes of differences. demonstrating AGE-induced crosslinking of extracellular matrix in diabetics, resulting in increased arterial stiffness. The fact that ADVANCES IN TREATMENT OF DIABETIC OCULAR SURFACE corneal thicknesses are elevated in children with DM who did not have other DM complications suggest that the cornea may be Systemic treatment in DM is the cornerstone of treatment in any 96,101 affected by AGE earlier than other organs. Nevertheless, it is diabetic complication. Tight blood glucose control, preferably in premature at present to speculate if corneal pachymetry, collaboration with an endocrinologist, can prevent further 63,114 commonly done in eye clinics, can be used to detect early DM progression of corneal epitheliopathy and neuropathy. changes. Insulin treatment in diabetic mice reduced the level of oxidative Given that AGE-related crosslinking of corneal proteins can stress in the lacrimal gland, assessed by total tissue peroxidase change the shape or morphology of the cornea in DM, is it and malonaldehyde levels. The newer therapeutics approaches possible that DM may influence specific eye disorders that proposed in recent years and their limitations are summarized in manifests with corneal biomechanical changes? One such Box 1. example is keratoconus, a degeneration of the cornea character- The aim of local treatment in diabetic keratopathy is to maintain ized by progressive ectasia or thinning of the cornea, typically a smooth and lubricated ocular surface with an intact epithelium presenting at teenage or early adult years. Unfortunately, the and adequate blink response. This minimizes visual distortion and published cross-sectional studies did not demonstrate a consistent maximizes comfort. The exact treatment prescribed is dependent association between DM and such alteration of corneal on the severity of the problem and the specific structures 93,94 shapes. involved. Early or mild disease will present as dry eye or recurrent erosions, and more severe disease in the form of neurotrophic ulcers and secondary infections. A step-wise approach towards CORNEA ENDOTHELIAL DISEASE treatment, such as that mentioned in the Dry Eye Workshop Apart from the epithelium, the innermost layer of the cornea, (DEWS), is helpful, aiming to halt further damage, encourage re- called the corneal endothelium, plays a vital role in keeping the epithelialization, prevent infection and maintain adequate lubrica- stroma dehydrated. This is because of the active pumping action tion of the ocular surface. of fluid from the cornea to the anterior chamber by the corneal A previous review has already described how therapies like endothelial cells. Similar types of regulated fluid transport are lubricants, antibiotics, autologous serum and anti-inflammatory extremely important in diabetes in other contexts, for example, in agents, as well as devices, such as bandage contact lenses in DM the kidney. patients. The benefit of autologous serum is that it contains Seven papers related to the corneal endothelium in DM have growth factors that may further enhance epithelial wound healing. been published in the review period and all were hospital-based An irregular ocular surface may benefit from a bandage contact Nutrition & Diabetes (2017) 1 – 10 Systemic review diabetes ocular surface KCo Shih et al Box 1 New systemic therapies Box 2 New topical therapies in diabetic ocular surface ● ● Resolvin-D1, an anti-inflammatory eicosanoid, reduced cor- Carnosine, an antioxidant, may be used to counter the effects neal and peripheral nerve degeneration in diabetic rats when of AGE in the ocular surface. Topical administration of the administered as an oral supplement together with menha- substance has been shown to be effective in maintaining den (fish) oil. The effect was independent of blood glucose thiol levels in the cornea of rats with induced diabetes. This levels. study unfortunately did not included assessment of the tear Beta carotene, an antioxidant, was shown to ameliorate function and health of the ocular surface by imaging. diabetes-related ultrastructural changes to the cornea in a rat Sericin and aloe vera are topical protective agents and 116 122,123 model. The beneficial effects of beta carotene was promote ocular surface wound healing. associated with a reduction in average blood glucose in Naltrexone, a long-acting opioid antagonist, administrated topically or orally has been shown to accelerate corneal treated groups. Ilepatril, a vasopeptidase inhibitor and new hypertension wound healing and restitute corneal sensitivity. It has also drug, can degrade vaso- and neuro-active petides as well as been shown to be safe and effective in more than one type 12,85,86,124,125 angiotension converting enzyme (ACE). In rats with of animal model. streptozotocin-induced diabetes, oral administration of Topical application of growth factors in diabetic animal models, in particular insulin and nerve growth factor (NGF), ilepatril protects against degeneration of the corneal 81,124 have had promising results. Insulin is a much cheaper nerves. Enalapril, an ACE inhibitor, in combination with alpha lipoic drug to produce than NGF, and therefore more likely to acid (antioxidant) and menhaden oil was shown to reverse widely adopted, but it does not protect against the loss of diabetic corneal and peripheral neuropathy in corneal sensitivity. Moreover NGF can be easily degraded by streptozotocin-induced diabetic rats when administrated alteration of temperature, pH and presence of tear 118 126 per-orally. proteases. ● ● KIOM-79 (a mixture of 80% ethanol extracts of parched Insulin-like growth factor 1 (IGF-1) promotes cell proliferation Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae and when administrated topically to type 2 diabetic mice. radix and Euphorbiae radix) can be used as an oral Improved corneal sub-basal nerve density compared with therapeutic agent by reducing AGE in tissues like the cornea. controls. Targeting microRNA miR-146Aa may be used to treat delays In a rat model of DM, it also reduced the downstream oxidative damage, nuclear factor kappa-B activation and Bax in wound healing in diabetic corneas, but this had been reported in organ cultures only. overexpression in the cornea. ● Experimental gene therapies may be a viable form of local Experimental stem cell therapy, in the form of human treatment for cornea disease in diabetics. Hepatic growth hematopoietic stem cells transplanted into the peritoneum of rats, reduced apoptosis in the corneal and conjunctival factor (HGF)-driven epithelial migration and wound closure is dependent on the function of the receptor tyrosine kinase epithelium. However, the corneal nerves were not examined in those experiments. It is important to note that c-Met. In DM animal models, the HGF levels were increased in the cornea epithelium, but the c-Met levels have decreased. such xenograft approaches also have to deal with the expected immune response against transplanted cells. Since inadequate c-Met levels may impair wound healing, adenoviral vector mediated overexpression of c-Met was attempted to correct the molecular anomaly. In organ- cultured human corneas from diabetic patients, the rate of lens to reduce further trauma. For more severe conditions epithelial migration was restored to the levels in the non- including neurotrophic ulcers, surgical options to induce eyelid diabetic corneas. Though promising, such therapies have closure, including botulinum toxin injection and tarsorrhaphy, numerous hurdles to overcome, including safety concerns may be required. Some of the newer treatment modalities directed to the ocular and issues related to the lack of specificity in delivery of 129–131 expression vectors. surface have been recently reviewed are summarized in Box 2. The challenge of maintaining therapeutic concentrations of any topical drugs on the ocular surface is the rapid dilution by resident tears and elimination through the nasolacrimal duct. therapies are promising but have not yet been translated to routine care. The bulk of the published work in these areas concerns evaluation in animal models and not clinical trials. CONCLUSION AND FUTURE STUDIES The future of diabetes management is dependent on increased The assessment of the diabetic ocular surface has implications awareness of the importance of the ocular surface in diabetes. An beyond eye care. Challenges and future directions in this field are improved understanding of the ocular surface among the general described in the Boxes 1 and 2. The corneal nerve parameters are medical profession is essential for optimal management. all age related and, therefore, widespread use of these features for screening patients will only be useful if age-stratified normative values are available for the target population. Reading centers CONFLICT OF INTEREST for corneal imaging will play a major role in such initiatives. Use of The authors declare no conflict of interest. special imaging techniques such as 2-photon microscopy in genetically modified mice with visible corneal nerves will be immensely valuable to investigate changes in animals with diabetic neuropathy, especially in the cornea. ACKNOWLEDGEMENTS Apart from more conventional approaches, newer therapeutic We would thank the Singapore Eye Research Institute and the University of Hong agents including targeted molecular therapy, gene and stem cell Kong for making this collaborative effort possible. 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To view a copy of this license, visit http://creativecommons.org/licenses/ in streptozotocin-induced type 1 diabetic rats: improvement with ilepatril by/4.0/ treatment. Invest Ophthalmol Vis Sci 2012; 53: 8067–8074. 118 Davidson EP, Holmes A, Coppey LJ, Yorek MA. Effect of combination therapy © The Author(s) 2017 consisting of enalapril, alpha-lipoic acid, and menhaden oil on diabetic Nutrition & Diabetes (2017) 1 – 10 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nutrition & Diabetes Springer Journals

A systematic review on the impact of diabetes mellitus on the ocular surface

Shih, K Co; Lam, K S-L; Tong, L
Nutrition & Diabetes , Volume 7 (3) – Mar 20, 2017
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Springer Journals
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Copyright © 2017 by The Author(s)
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Medicine & Public Health; Medicine/Public Health, general; Diabetes; Clinical Nutrition; Epidemiology; Metabolic Diseases; Internal Medicine
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10.1038/nutd.2017.4
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Abstract

OPEN Citation: Nutrition & Diabetes (2017) 7, e251; doi:10.1038/nutd.2017.4 www.nature.com/nutd REVIEW A systematic review on the impact of diabetes mellitus on the ocular surface 1,2 2,3,4 5,6,7,8 K Co Shih , KS-L Lam and L Tong Diabetes mellitus is associated with extensive morbidity and mortality in any human community. It is well understood that the burden of diabetes is attributed to chronic progressive damage in major end-organs, but it is underappreciated that the most superficial and transparent organ affected by diabetes is the cornea. Different corneal components (epithelium, nerves, immune cells and endothelium) underpin specific systemic complications of diabetes. Just as diabetic retinopathy is a marker of more generalized microvascular disease, corneal nerve changes can predict peripheral and autonomic neuropathy, providing a window of opportunity for early treatment. In addition, alterations of immune cells in corneas suggest an inflammatory component in diabetic complications. Furthermore, impaired corneal epithelial wound healing may also imply more widespread disease. The non- invasiveness and improvement in imaging technology facilitates the emergence of new screening tools. Systemic control of diabetes can improve ocular surface health, possibly aided by anti-inflammatory and vasoprotective agents. Nutrition & Diabetes (2017) 7, e251; doi:10.1038/nutd.2017.4; published online 20 March 2017 INTRODUCTION reviews) and 110 relevant original articles. For example, articles that involved only the posterior segment of the eye (retina, Diabetes mellitus (DM) is a significant public health problem. It is vitreous) or involving only ‘diabetes insipidus’ and not ‘diabetes estimated that more than 342 million people worldwide will suffer mellitus’ would be considered irrelevant. A total of 106 were from DM by 2030 and the total health burden incurred by DM will deemed irrelevant. be driven by the severity of diabetic complications in different organs. The ocular surface, including the superficial and transpar- ent cornea, is known to be involved in diabetes in various ways: CORNEA EPITHELIAL DISEASE AND OCULAR SURFACE this includes common diseases like dry eye and recurrent corneal 1 ABNORMALITIES erosions, previously reviewed elsewhere. However, new research It is known that diabetes is associated with impaired wound beyond 2008 has not been systematically reviewed, even after the 2–19 healing. This is evident in the corneal epithelium. Diabetic eyes are emergence of fairly recent review articles. This is an important at increased risk of dry eye, superficial punctate keratitis, recurrent issue to address as new developments such as cellular, molecular 20,21 corneal erosion syndrome and persistent epithelial defects. As biology and animal genetics have advanced considerably in the the corneal epithelium is the first layer of the eye, it is constantly last few years. Here, we provide a systematic review of the recent subjected to wear and tear and it needs to be constantly literature (published 2009–2015), which enlightens on the role of regenerated. Any process that affects wound healing or the speed the ocular surface and cornea in DM (Figure 1) and research on of epithelial regeneration will have physiological impact and potential treatment strategies. 22–25 increases morbidity including ocular pain and redness. Recently a human study conducted in a hospital showed for the first time that tear levels of type 1 and 2 diabetic individuals had MATERIALS AND METHODS significantly higher insulin-like growth factor binding protein A literature search was conducted on the 5th of January 2016 in (IGFBP3) compared with age-matched normal adults. IGFBP3 is a the NCBI Entrez Pubmed database and included search terms multifunctional protein that is known to play a negative regulatory diabetes and cornea. Articles were limited to journal articles in role in IGF signaling by binding and sequestrating it, competing which the keywords ‘cornea’ or ‘conjunctiva’ occur in conjunction with its cellular receptor IGFR-1. In the wider context, IGFBP3 has with the keyword ‘diabetes’ in the textword (tw) field of the been known to regulate insulin resistance, apoptosis as well as search. We only examined journal articles published between 1st oxidative damage. The processes regulating the secretion of of January 2009 and 31st of December 2016. The 234 articles IGFBP3 from corneal epithelial tissue is not known, but in identified were then curated by two coauthors (KS and LT) for experiments with immortalized human corneal epithelial cells, it relevance, via abstract or the full text of the article, and this was found that high levels of glucose in the culture medium can produced a list of 23 review articles, letters or commentaries (18 induce the production of IGFBP3, suggesting that the 1 2 Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Research Center of Heart, Brain, Hormone and Healthy 3 4 Aging, The University of Hong Kong, Hong Kong; Department of Medicine, The University of Hong Kong, Hong Kong; State Key Laboratory of Pharmaceutical Biotechnology, 5 6 The University of Hong Kong, Hong Kong; Singapore Eye Research Institute, National Eye Centre, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, 7 8 Singapore; Department of Ophthalmology, Singapore National Eye Center, Singapore and Department of Ophthalmology, Duke-NUS Medical School, Singapore. Correspondence: Dr L Tong, Department of Ophthalmology, Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751, Singapore. E-mail: [email protected] Received 5 October 2016; revised 10 November 2016; accepted 14 November 2016 Systemic review diabetes ocular surface KCo Shih et al Figure 1. Schematic showing pathogenesis of corneal disease in diabetes mellitus. Hyperglycemia and formation of advanced glycation end products have distinct effects on different parts of the cornea, resulting in three principal types of tissue dysfunction with physiological effects that can be measured. (1) Defective wound healing in the corneal epithelium, (2) abnormalities of sub-basal nerves and (3) loss of corneal endothelial pump function. (1) Raised blood glucose promotes IGFBP3 release, which in turn competitively inhibits IGF-1, whereas TGFb3, EGFR, CNTF are suppressed in hyperglycemic states. The consequential reduction in epithelial cell proliferation and increased apoptosis impacts on epithelial wound healing. (2) Neuronal damage is a key defect in diabetes mellitus. Prolonged hyperglycemia results in the accumulation of advanced glycation end products which promotes inflammation and oxidative stress. NGF and sphingolipids are key to neuronal health and myelin formation, but their production are inhibited in hyperglycemic states. (3) Prolonged hyperglycemia also results in endothelial cell loss and impairment in pump function. Apart from these processes, the swelling of the corneal stroma (the main bulk of the cornea) may be due to loss of epithelial barrier, crosslinking of stromal collagen and matrix, and loss of the endothelial pump. CNTF, ciliary neurotrophic factor; EGFR, epithelial growth factor receptor; IGF-1, insulin-like growth factor 1; NF-kB, nuclear factor kappa-light-chain- enhancer of activated B cells transcription factor; NGF, nerve growth factor; TGFb3, transforming growth factor beta-3. Solid blue arrows— activation/promotion, red stop arrows—inhibition or negative regulation. hyperglycemia in patients may be the cause of the IGFBP3 Use of diabetic animals has both advantages and constraints. upregulation. This paper did not examine other potential sources The obvious advantage is the ability to obtain ocular tissue, but of IGFBP3 such as lacrimal glands and immune cells. In addition, the main advantage of using these models is the possibility of the clinical examination results of the corneal epithelium of the examining changes before and after induction of diabetes. Such changes are almost impossible to evaluate in human patients as participants such as presence of epitheliopathy were not they would not have come to the attention of health professionals reported. 27,28 prior to the development of diabetes. The major limitation of Two studies with C57 db/db mice and four studies involving 24,29–31 animal models is that the induction of DM occurs fairly rapidly rats showed that hyperglycemia induced detrimental using one intervention compared with the more chronic, multi- effects on the cornea epithelium-basement membrane complex. factorial DM in humans, and therefore the disturbance may not be In these studies, decreases in corneal epithelial function were translatable to human disease. Induction of diabetes may be via documented by an increase in corneal thickness, and structural 24,29,30 injection of streptozotocin in Sprague Dawley (SD) rats, or in some changes were examined by electron microscopy. Since the cases, rats may be naturally diabetic such as Otsuka Long-Evans normal corneal epithelium plays an important barrier function Tokushima fatty (OLETF) rats. Streptozotocin destroys beta islet in excluding water from entering the stroma, a reduction in cells in the pancreas of the animals, with reduction of insulin the barrier function will manifest as edema and swelling secretion and consequent hyperglycemia. The hyperglycemia- of the normally relatively dehydrated stroma. The component of related effects as well as the oxidative stress associated with the epithelium forming the barrier is largely sub-served by tight ingestion of fat and ethanol in OLEFT rats then induce systemic junctional complexes between cornea epithelial cells, visualized as organ damage. electron dense structures. Loss or disruption of these tight One of the molecular changes detected in animal eyes is the junction structures or loss of basal corneal epithelial cells on measurement of levels of advanced glycation end products imaging would explain loss of epithelial function. The loss of (AGE). This is an important pathological outcome as it is epithelial function can affect vision because the onset of edema considered to be the mediator for all chronic DM complications causes cornea opacification and will directly affect transmission of including macrovascular and microvascular complications such as light through the cornea. diabetic retinopathy in the eye. The accumulation of AGE in the Nutrition & Diabetes (2017) 1 – 10 Systemic review diabetes ocular surface KCo Shih et al cornea epithelium-basement membrane shifts local cell signaling Specific nerve indices may have been found to be useful in a towards pro-apoptotic and antiproliferative pathways, as well as particular region of the cornea for some clinical scenarios. Analysis 44–49 increases oxidative stress and inflammation. A typical way of of the sub-basal nerve plexus can be performed in two regions of the cornea: central cornea and the inferior whorl. For measuring oxidative stress in the ocular surface tissue is the example, it has also been reported that the nerve fiber density at quantification of the level of the oxidized nucleotide 8- the inferior whorl region is more sensitive to early nerve fiber hydroxydeoxyguanosine. A separate study found the gamma- damage than the central corneal region, in DM patients before glutamyl transferase level in the tear to be reduced in 14 type 1 development of peripheral neuropathy. and 2 DM participants compared with 14 control participants. Scans can be evaluated manually (CCModule), in semiauto- However, in cornea buttons of cadavers, the tissue levels of the mated fashion (NeuronJ) or in a fully automated (ACCModule) enzyme were lower in type 1 DM than in type 2 DM and controls. 52,53 technique. All three methods were reported to have high While these are interesting results in view of the possible role of repeatability, which can be further improved with experience but the transferase in oxidative stress, more studies are required to 54–60 33 not by increasing magnification. The speed of image analysis determine the mechanistic significance. can be improved with use of automated quantification techniques As DM is a chronic disease, it is important to differentiate 13,61,62 as well as wide-field imaging. Calculations from full molecular changes that induce the disease as opposed to automation are well correlated to those by manual methods, molecules that mediate secondary complications. Distinct ultra- and so may be useful in communities without a manual structural tissue alterations may occur in pre-diabetic eyes as well evaluator. 29 23,28 as in established DM. Here in vitro studies and animal models are useful to chart the temporal changes as the corneal Clinical studies levels of epithelial growth factor receptor, ciliary neurotrophic factor and nuclear factor kappa B may be determined at different It is well known for many years that corneal nerve density is reduced in type 1 DM. Recently both types of DM have been stages of disease. TGFb3, epithelial growth factor receptor and associated with reduction of corneal nerve density and other ciliary neurotrophic factor have already been found to promote 19,45,47,63–65 corneal nerve abnormalities (Table 1). corneal epithelial wound healing in studies on wound healing and Reduction in corneal nerve fiber density is a characteristic found to be reduced in corneas of diabetic animals. The nuclear manifestation of diabetic corneal neuropathy, with demonstrated factor kappa B on the other hand is an important transcription progression over time, in a 4 year cohort study of DM participants factor that affects inflammation and cell development found to be 34–36 from two countries (Australia and UK). increased in corneas of diabetic animals. An interesting question would be whether good glycemic control restores the corneal nerve innervation and dysfunction? CORNEA NEUROPATHY Two clinical cohort studies have concluded that once DM (type 1 and type 2) was established, good glycemic control was able to The sensory innervation of the cornea is a major determinant of 67,68 improve but not completely reverse corneal neuropathy. epithelial health and healing capacity. This may be mediated by Corneal nerve parameters have been found to correlate to secretion of substance P by the nerves and binding to neurokinin- diabetic peripheral neuropathy and autonomic neuropathy 1 receptor on the epithelial cells. Corneal nerves are branches of 43,46,48,49,66,69–73 (Table 2). Diabetic peripheral neuropathy, a the ophthalmic nerve, which is a branch of the trigeminal cranial common complication in up to 54% of diabetic population, is a nerve. They perforate the corneal stroma at the medial and lateral significant cause of morbidity and poor quality of life in diabetic positions and branch into neurites that eventually sprout nerve 3 patients. As such, early detection of high-risk patients can pre- endings anteriorly into the corneal epithelium. empt the course of the disease with measures such as better foot- The cornea is the most densely innervated structure in humans, care to improve healthcare outcomes. with nerve fibers playing an important neurotrophic role in the Conventional clinical diagnosis of diabetic peripheral neuro- development of a healthy corneal surface. Loss of neurotrophic pathy includes clinical assessment and nerve conduction studies. function may result in a non-healing or persistent cornea epithelial However, these tests detect large fiber deficits, rather than the defect or neurotrophic ulcer. This has associated cornea edema small unmyelinated C and thinly myelinated Aδ-nerve fibers which and disturbance of visual function and is an important cause of 15,74–76 are affected earlier in the course of the disease. The higher morbidity in cornea clinics. density and the preponderance of small nerve fibers in the cornea Unlike other areas of the body, corneal nerves can be easily may explain why corneal nerve fiber changes can be detected visualized in the transparent anterior corneal stroma by modern before awareness of diabetic peripheral neuropathy in the lower imaging techniques in clinical scenarios without invasive biopsy 6,16,17,45,77 limbs. Decreases in nerve fiber length in sub-basal nerve procedures. Essentially the in vivo findings have been confirmed plexus have also been found to be associated with subclinical by cadaveric ex vivo studies. diabetic autonomic neuropathy which may be life-threatening, including cardiovascular complications such as arrhythmias or 46,71,72 Advances in confocal imaging techniques sudden cardiac deaths. The vagal function is used as a measure of autonomic neurological function, assessed by the The most important advance in the last few years is the use of change of heart rate in response to breathing and posture. modern scanning laser ophthalmoscopy. The most common form of this in vivo confocal microscopy is the Heidelberg Retinal Tomography (Heidelberg, Germany), which is performed in Mechanisms of corneal neuropathy 10,11,14,41 conjunction with a corneal modular lens. Images acquired Broadly, peripheral neuropathies are considered microvascular DM are processed by imaging software for indices of nerve fiber complications as a result of nerve ischemia. The conventional view density, nerve fiber length, nerve branch density and nerve is that AGE initiates damage to the pericytes and endothelium of tortuosity in the sub-basal nerve plexus because changes in this capillaries and reduces microvascular supply to Schwann cells or layer are more relevant in DM than in intrastromal nerves. One neurons. This consequently decreases neuronal function. If the research group used NeuronJ, a plug-in for the NIH freeware status of corneal nerves reflects peripheral nerve status, under- 43 3 Image J whereas the other group used proprietary ACModule standing the mechanism of the corneal neuropathy is vital. and CCModule software developed in the University of Microvascular abnormalities occur in the retina as well as in the Manchester. cornea. Reduction of corneal nerve fiber density or length have Nutrition & Diabetes (2017) 1 – 10 Systemic review diabetes ocular surface KCo Shih et al Table 1. Studies comparing corneal nerve parameters in diabetic subtypes a b c Source Country Groups Sample size Method Parameter (mean) Outcomes Associations − 2 Messmer et al. Germany Type I and II 13/54/24 HRT II NFD (no. mm ) DM1/DM2/C: Increasing severity of nerve fiber 45 −2 (2010) DM vs Image J NFL (mm mm ) 16.9/16.1/23.3 parameters with higher stages of −2 controls Esthesiometer NBD (no. mm ) 9.7/10.7/16.1 diabetic retinopathy, history of NT 1.5/1.6/1.4 nephropathy, peripheral neuropathy, and decreased corneal sensation predictive of abnormal CCM parameters, first paper to demonstrate abnormal CCM parameters in patients with normal corneal and vibration sensation −2 Ischibashi et al. Japan Type I DM vs 38/38 HRT III NFD (no. mm ) DM1/C: HbA1c level and blood pressure were 63 −2 (2012) controls Image J NFL (mm mm ) 25.32/36.62 an independent negative predictors of NT 9.80/13.65 NFL and NFD Beading (mm) 3.13/1.74 22.38/30.44 −2 Nitoda et al. Greece Type II DM 46/47/46/47 HRT II, NFD (no. mm ) DM2 noDR/NPDR/ Positive correlation between corneal 47 −2 (2012) (noDR/ MATLAB NBD (no. mm ) PDR/C: neuropathy and peripheral neuropathy −2 NPDR/NPDR/ NFL (mm mm ) 27.4/23.7/18.8/31.3 PDR) vs NT 39.9/30.6/25/45.1 controls 14.8/12.3/10.4/16.6 1.8/1.9/1.9/1.7 −2 Zhivov et al. Germany DM vs 36/20 HRT II NFD (mm mm ) DM/C: No difference in CCM parameters 64 −2 (2013) controls GIMP NFL (mm mm ) 0.006/0.020 between patients with or without −2 Non-invasive NBD (no. mm ) 6.22/19.99 diabetic retinopathy, corneal sensation esthesiometer 25.3/141.9 was significantly lower in the diabetic group than in controls −2 Wang et al. China Type II DM 45/50 — NFL (mm mm ) DM2/C: Pain severity of diabetic peripheral 19 −2 (2014) vs controls NBD (no. mm ) 11/13 neuropathy showed negative NT 47/62 3.2/2.8 correlation with NFL and NBD, positive correlation with NT −2 Ziegler et al. Germany Type II DM 86/48 HRT II NFL (mm mm ) DM2/C: 65 −2 (2014) vs controls — NFD (no. mm ) 19.7/24.9 −2 Esthesiometer NBD (no. mm ) 299.2/397.3 165.2/226.7 a b Abbreviations: DM, diabetes mellitus; DR, diabetic retinopathy; NPDF, non-proliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. NBD, nerve branch density; NFD, nerve fiber density; NFL, nerve fiber length; NT, nerve tortuosity. C, control; DM1, type 1 diabetes mellitus; DM2, type 2 diabetes melliltus. been shown to predict the development of diabetic retinopathy as evaluation of corneal sensitivity which is a functional outcome of 45,47,78 well as sight-threatening retinopathy. nerve innervation. These studies, except one, employed Cochrat The formation of AGE may not be the initial trigger for pericyte Bonnet esthesiometry, which may not be as sensitive as a gas or damage or neuronal loss. Inflammation may play a role as high Belmonte esthesiometry. Nevertheless, the studies were able to concentrations of Langerhans cells and dendritic cells, the main find an association between corneal nerve parameters and corneal 6,46,49,75,76,79 antigen-presenting cells in the ocular surface, aggregate around sensitivity. 79,80 corneal nerve fibers early in the disease process. In addition, It is also well known that apart from being neurotrophic, loss of levels of neurotrophic factors may be reduced in DM, for example, corneal sensation also reduced lacrimal tear production since the reduction in serum nerve growth factor and lipids such as corneal receptors are the afferent limb of the lacrimal reflex arc. sphingolipids have been detected in diabetic eyes compared with The reduction of corneal innervation has been linked to abnormal 81,82 controls. tear function as well as more frequent and severe symptoms of 9,21,27,43,83–86 The cause or extent of immune dysfunction, if any, in humans dry eye in DM patients. These studies included those with type 2 DM is not known. It has been found that immune cell with or without previous surgical procedures such as LASIK and infiltration of animal corneas may precede the induced hypergly- cataract surgeries. In one study, abnormal corneal innervation cemia (ARVO 2015 e-abstract 3076). In fact, in a longitudinal rat manifested as tear film dysfunction and debilitating, chronic study, the pre-diabetic obese rats have already manifested a irritation of the eye in type 1 but not in type 2 DM. similar amount of corneal nerve abnormalities with the diabetic rats. This suggests that accumulation of AGE, which is CORNEA STROMA AND BIOMECHANICS dependent on hyperglycemia and not present in pre-diabetic animals, is unlikely to be the cause of immune dysfunction in The corneal structure underneath the epithelium and the these animals. More animal studies with a mechanistic approach Bowman’s layer is called the stroma. The corneal stroma is would be necessary to determine the cause of immune important because it accounts for 90% of the thickness of the dysfunction in DM. cornea and therefore its tensile strength and biomechanical Do changes in corneal nerve structure lead to functional properties in general. The thickness of the human cornea is the alteration? To answer this question the newer studies in Tables 1 most frequently measured parameter in clinical biometry of the and 2 also included corneal esthesiometry. This is a method of eye. The main novelty in the recent clinical papers on corneal Nutrition & Diabetes (2017) 1 – 10 Systemic review diabetes ocular surface KCo Shih et al Table 2. Studies comparing corneal nerve parameters in different stages of diabetic peripheral neuropathy a c Source Country Groups Sample size Method Parameter Outcomes Associations (mean) −2 Edwards et al. UK and Type I DM 143/88/61 HRT III NFL (mm mm ) DM1/C: 18.3/16/20 Baseline findings of longitudinal 69 −2 (2012) Australia (without CCMetrics NBD (no. mm ) 69/58/80 study: NFL and NBD strongly PN/with NT 0.22/0.23/0.21 correlated with nerve DPN) vs conduction study parameters, controls NFL inversely correlated with HbA1c and duration diabetes −2 Petropoulos UK DM (no 50/26/ HRT III NFD (no. mm ) noPN/modPD/sev PN/C: Symmetrical reduction in CCM 48 −2 et al. (2013) PN/mild 17/18/47 CCMetrics NBD (no. mm ) 26.9/23.25/18.9/13.1/36.95 parameters for all groups except −2 PN/mod NFL (mm mm ) 55.5/48.25/32.4/19.6/96.55 those with severe neuropathy PN/sev PN) NT 20.05/17.6/14.7/9.75/27.25 vs controls 18.2/21.2/18.45/16.45/16.4 −2 Pritchard et al. UK and Type I DM 166/76/154 HRT III NFL (mm mm ) DM2/C: 19/13/23 Baseline of longitudinal study, 49 −2 (2014) Australia (without CCMetrics NBD (no. mm ) 60/40/80 reduction in corneal nerve fiber PN/with Esthesiometry length already noted in DM DPN) vs patients without peripheral controls neuropathy, reduction in corneal sensitivity only in type I DM patients with peripheral neuropathy −2 Stem et al. USA DM (no 25/10/8/9 HRT II NFL (mm mm ) noPN/midPN/severe (2014) PN/mild NeuronJ PN/C: 15.1/18.5/12.5/20.7 PN/severe PN) vs controls −2 DeMill et al. USA DM (no or 16/9/9 HRT II NFL (mm mm ) noPN/severe PN/C: 18/12/ Tear osmolarity increases and (2015) mild PN/ NeuronJ 20.5 NFL decreases with increasing severe PN) Esthesiometry severity of PN, DM patients had vs controls lower Schirmer's test values than controls, no differences in OSDI or VFQ-25 scores, TBUT and ocular surface staining between groups −2 Tavakoli et al. UK DM 15/19/18 Confoscan P4 NFD (no. mm ) noAN/AN/C: 35.70/48.26 CCM findings correlated 71 −2 (2015) (without NBD (no. mm ) 21.24/30.09 7.08/9.74 significantly with autonomic −2 AN/with NFL (mm mm ) symptoms (COMPASS and CASS) AN) vs controls Misra et al. New Type I DM 53/40 HRT II Sub-basal nerve DM1/C: 11/21.17 Negative correlation between (2015) Zealand vs controls analySIS 3.1 density corneal sensitivity and −2 Esthesiometry (mm mm ) autonomic nerve function, 50% of patients with abnormal CCM findings had otherwise no evidence of peripheral or autonomic neuropathy −2 Maddaloni Italy Type I DM 36/20 Confoscan 4, NFD (no. mm ) noAN/AN/C: 51.7/32.8/92 CCM findings lower in DM 72 −2 et al. (2015) (without Image J NFL (mm mm ) 1.4/1.9/1.4 patients with autonomic AN/with Beading (mm) 14.8/15.3/20.6 neuropathy than those without AN) vs controls −2 Dehghani Australia Type I DM 147/60 HRT III, NFD (no .mm ) noPN/withPN/C: Baseline (left). Prospective: 66 −2 et al. (2014) (without ACCMetrics NBD (no. mm ) 18.3/16.3/22.3 significant annual reduction in −2 PN/with NFL (mm mm ) 24.2/23.7/35.1 nerve fiber density in PN group PN) vs 16/15/18.1 vs controls (−0.9 per mm per controls year vs − 0.06 per mm per year) CCM findings correlated with peroneal nerve conduction velocity (r= 0.38) and cold sensation threshold (r = 0.40) −2 Chen et al. UK Type I DM 63/26 HRT III NFD (no. mm ) noPN/withPN/C: Comparable diagnostic efficacy 73 −2 (2015) (without CCMetrics NBD (no. mm ) 28.3/16.9/36.8 between confocal microscopy −2 PN/with ACMetrics NFL (mm mm ) 56.1/48.2/56.1 measurements and −2 PN) vs NFD (no. mm ) 20.2/14.8/26.7 intraepidermal nerve fiber −2 controls NBD (no. mm ) 22.6/13.5/31.3 density (via skin biopsy, gold −2 NFL (mm mm ) 26.2/15.4/44.6 standard) 13.4/8.8/17.7 a b Abbreviations: AN, diabetic autonomic neuropathy; DM, diabetes mellitus; PN, diabetic peripheral neuropathy. NBD, nerve branch density; NFD, nerve fiber density; NFL, nerve fiber length; NT, nerve tortuosity. C, control; DM1, type 1 diabetes mellitus; DM2, type 2 diabetes melliltus. Nutrition & Diabetes (2017) 1 – 10 Systemic review diabetes ocular surface KCo Shih et al biomechanics involved the assessment of corneal hysteresis and studies, except for one study comparing endothelial counts 105–112 resistance force, due to the recent availability of the Ocular between diabetic and non-diabetic cadaveric donors. The 84,88,89 Response Analyser, which can quantify these two para- biggest study of the 5, conducted in Vellor, India, involved 153 meters. Hysteresis refers to the amount of force required to indent participants with DM and 163 age-matched controls, and was the cornea as well as the recovery from the indentation. performed on patients before and after cataract surgery up to Resistance force is the hysteresis normalized to the cornea shape. 3 months postoperatively. Preoperative examinations showed A higher hysteresis suggests a more rigid and less deformable no statistically significant difference between the groups in any of cornea. Seven cross-sectional clinic-based studies in Western the corneal endothelial parameters. Both DM and controls had 87,90–92 93 89 88 94 Europe, United States, Brazil, Israel and Iran have decreases in endothelial counts and increase in morphological found type 1 and type 2 DM participants to have higher hysteresis, abnormalities (increase in cell sizes or polymegathism and whereas only one study (Turkish study) found them to have a increased variability of shape called pleomorphism) at 6 weeks lower hysteresis, compared with age-matched controls. In one and 3 months post-operation. The authors reported that in the study, it was found that the fasting blood glucose level was control group the rate of loss of corneal endothelial cells between significantly but weakly correlated (r = 0.28) to the corneal 6 weeks and 3 months was relatively milder compared with the hysteresis. DM group (P = 0.023). However, the actual measurements were Two other studies published in this recent period on corneal not significantly different at any time points, suggesting that none morphology found DM to be associated with a greater corneal of the differences discovered were clinically relevant. It is worth 96–98 thickness, which was consistent with reports earlier than noting that this Indian study evaluated only small incision manual 2008. It is noteworthy that patients with proliferative, non- cataract surgery but did not investigate phacoemulsification; the proliferative retinopathies and those with no diabetic retinopa- latter is the more common form of surgery in the developed world thies did not have significantly different corneal and potentially induces more corneal endothelial cell loss than 90,97–100 113 thicknesses. In addition, a study in 100 children aged 6– manual surgery. 17 years with type 1 DM in Romania had an increase in corneal The other five papers were cross-sectional studies conducted in 105–109 thickness compared with an equivalent number of children of the Korea, Malaysia and Hungary, Poland and Denmark. These 101 96 same age, and similar findings had been reported in Turkey. studies excluded participants with prior cataract surgery or history The reason why DM is associated with greater corneal hysteresis of ocular disease, and reported statistically significant association or thicknesses is not completely known, apart from the relation- of type 2 DM with increased clinical features of corneal endothelial ship between increased corneal thicknesses in cases of overt dysfunction (reduced endothelial count, and polymegathism and corneal epitheliopathy. However, it has been speculated that the pleomorphism). Nevertheless, the magnitude of the reported accumulation of AGE in the cornea stroma of diabetics may occur differences between the DM and age-matched controls in these together with non-enzymatic crosslinking between collagen studies was very small. For example, in the Malaysian study, the molecules and proteoglycans. The crosslinking would theoretically mean corneal endothelial counts was 2541 cells per mm in DM explain stiffening and thickening of the cornea. One study compared with 2660 cells per mm in controls, with a difference of compared eight monkeys with insulin-dependent diabetes about 120 cells per mm . By excluding participants with (streptozotocin injection) to four controls. In the diabetic eyes ophthalmic problems, these studies would have included only crosslinking has manifested ultra-structurally as abnormal collagen participants with shorter duration of DM. Had these studies fibril aggregates in the stromal matrix on transmission electron recruited DM participants with longer durations, it may be microscopy. This is consistent with published evidence possible to discover greater magnitudes of differences. demonstrating AGE-induced crosslinking of extracellular matrix in diabetics, resulting in increased arterial stiffness. The fact that ADVANCES IN TREATMENT OF DIABETIC OCULAR SURFACE corneal thicknesses are elevated in children with DM who did not have other DM complications suggest that the cornea may be Systemic treatment in DM is the cornerstone of treatment in any 96,101 affected by AGE earlier than other organs. Nevertheless, it is diabetic complication. Tight blood glucose control, preferably in premature at present to speculate if corneal pachymetry, collaboration with an endocrinologist, can prevent further 63,114 commonly done in eye clinics, can be used to detect early DM progression of corneal epitheliopathy and neuropathy. changes. Insulin treatment in diabetic mice reduced the level of oxidative Given that AGE-related crosslinking of corneal proteins can stress in the lacrimal gland, assessed by total tissue peroxidase change the shape or morphology of the cornea in DM, is it and malonaldehyde levels. The newer therapeutics approaches possible that DM may influence specific eye disorders that proposed in recent years and their limitations are summarized in manifests with corneal biomechanical changes? One such Box 1. example is keratoconus, a degeneration of the cornea character- The aim of local treatment in diabetic keratopathy is to maintain ized by progressive ectasia or thinning of the cornea, typically a smooth and lubricated ocular surface with an intact epithelium presenting at teenage or early adult years. Unfortunately, the and adequate blink response. This minimizes visual distortion and published cross-sectional studies did not demonstrate a consistent maximizes comfort. The exact treatment prescribed is dependent association between DM and such alteration of corneal on the severity of the problem and the specific structures 93,94 shapes. involved. Early or mild disease will present as dry eye or recurrent erosions, and more severe disease in the form of neurotrophic ulcers and secondary infections. A step-wise approach towards CORNEA ENDOTHELIAL DISEASE treatment, such as that mentioned in the Dry Eye Workshop Apart from the epithelium, the innermost layer of the cornea, (DEWS), is helpful, aiming to halt further damage, encourage re- called the corneal endothelium, plays a vital role in keeping the epithelialization, prevent infection and maintain adequate lubrica- stroma dehydrated. This is because of the active pumping action tion of the ocular surface. of fluid from the cornea to the anterior chamber by the corneal A previous review has already described how therapies like endothelial cells. Similar types of regulated fluid transport are lubricants, antibiotics, autologous serum and anti-inflammatory extremely important in diabetes in other contexts, for example, in agents, as well as devices, such as bandage contact lenses in DM the kidney. patients. The benefit of autologous serum is that it contains Seven papers related to the corneal endothelium in DM have growth factors that may further enhance epithelial wound healing. been published in the review period and all were hospital-based An irregular ocular surface may benefit from a bandage contact Nutrition & Diabetes (2017) 1 – 10 Systemic review diabetes ocular surface KCo Shih et al Box 1 New systemic therapies Box 2 New topical therapies in diabetic ocular surface ● ● Resolvin-D1, an anti-inflammatory eicosanoid, reduced cor- Carnosine, an antioxidant, may be used to counter the effects neal and peripheral nerve degeneration in diabetic rats when of AGE in the ocular surface. Topical administration of the administered as an oral supplement together with menha- substance has been shown to be effective in maintaining den (fish) oil. The effect was independent of blood glucose thiol levels in the cornea of rats with induced diabetes. This levels. study unfortunately did not included assessment of the tear Beta carotene, an antioxidant, was shown to ameliorate function and health of the ocular surface by imaging. diabetes-related ultrastructural changes to the cornea in a rat Sericin and aloe vera are topical protective agents and 116 122,123 model. The beneficial effects of beta carotene was promote ocular surface wound healing. associated with a reduction in average blood glucose in Naltrexone, a long-acting opioid antagonist, administrated topically or orally has been shown to accelerate corneal treated groups. Ilepatril, a vasopeptidase inhibitor and new hypertension wound healing and restitute corneal sensitivity. It has also drug, can degrade vaso- and neuro-active petides as well as been shown to be safe and effective in more than one type 12,85,86,124,125 angiotension converting enzyme (ACE). In rats with of animal model. streptozotocin-induced diabetes, oral administration of Topical application of growth factors in diabetic animal models, in particular insulin and nerve growth factor (NGF), ilepatril protects against degeneration of the corneal 81,124 have had promising results. Insulin is a much cheaper nerves. Enalapril, an ACE inhibitor, in combination with alpha lipoic drug to produce than NGF, and therefore more likely to acid (antioxidant) and menhaden oil was shown to reverse widely adopted, but it does not protect against the loss of diabetic corneal and peripheral neuropathy in corneal sensitivity. Moreover NGF can be easily degraded by streptozotocin-induced diabetic rats when administrated alteration of temperature, pH and presence of tear 118 126 per-orally. proteases. ● ● KIOM-79 (a mixture of 80% ethanol extracts of parched Insulin-like growth factor 1 (IGF-1) promotes cell proliferation Puerariae radix, gingered Magnoliae cortex, Glycyrrhizae and when administrated topically to type 2 diabetic mice. radix and Euphorbiae radix) can be used as an oral Improved corneal sub-basal nerve density compared with therapeutic agent by reducing AGE in tissues like the cornea. controls. Targeting microRNA miR-146Aa may be used to treat delays In a rat model of DM, it also reduced the downstream oxidative damage, nuclear factor kappa-B activation and Bax in wound healing in diabetic corneas, but this had been reported in organ cultures only. overexpression in the cornea. ● Experimental gene therapies may be a viable form of local Experimental stem cell therapy, in the form of human treatment for cornea disease in diabetics. Hepatic growth hematopoietic stem cells transplanted into the peritoneum of rats, reduced apoptosis in the corneal and conjunctival factor (HGF)-driven epithelial migration and wound closure is dependent on the function of the receptor tyrosine kinase epithelium. However, the corneal nerves were not examined in those experiments. It is important to note that c-Met. In DM animal models, the HGF levels were increased in the cornea epithelium, but the c-Met levels have decreased. such xenograft approaches also have to deal with the expected immune response against transplanted cells. Since inadequate c-Met levels may impair wound healing, adenoviral vector mediated overexpression of c-Met was attempted to correct the molecular anomaly. In organ- cultured human corneas from diabetic patients, the rate of lens to reduce further trauma. For more severe conditions epithelial migration was restored to the levels in the non- including neurotrophic ulcers, surgical options to induce eyelid diabetic corneas. Though promising, such therapies have closure, including botulinum toxin injection and tarsorrhaphy, numerous hurdles to overcome, including safety concerns may be required. Some of the newer treatment modalities directed to the ocular and issues related to the lack of specificity in delivery of 129–131 expression vectors. surface have been recently reviewed are summarized in Box 2. The challenge of maintaining therapeutic concentrations of any topical drugs on the ocular surface is the rapid dilution by resident tears and elimination through the nasolacrimal duct. therapies are promising but have not yet been translated to routine care. The bulk of the published work in these areas concerns evaluation in animal models and not clinical trials. CONCLUSION AND FUTURE STUDIES The future of diabetes management is dependent on increased The assessment of the diabetic ocular surface has implications awareness of the importance of the ocular surface in diabetes. An beyond eye care. Challenges and future directions in this field are improved understanding of the ocular surface among the general described in the Boxes 1 and 2. The corneal nerve parameters are medical profession is essential for optimal management. all age related and, therefore, widespread use of these features for screening patients will only be useful if age-stratified normative values are available for the target population. Reading centers CONFLICT OF INTEREST for corneal imaging will play a major role in such initiatives. Use of The authors declare no conflict of interest. special imaging techniques such as 2-photon microscopy in genetically modified mice with visible corneal nerves will be immensely valuable to investigate changes in animals with diabetic neuropathy, especially in the cornea. ACKNOWLEDGEMENTS Apart from more conventional approaches, newer therapeutic We would thank the Singapore Eye Research Institute and the University of Hong agents including targeted molecular therapy, gene and stem cell Kong for making this collaborative effort possible. 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To view a copy of this license, visit http://creativecommons.org/licenses/ in streptozotocin-induced type 1 diabetic rats: improvement with ilepatril by/4.0/ treatment. Invest Ophthalmol Vis Sci 2012; 53: 8067–8074. 118 Davidson EP, Holmes A, Coppey LJ, Yorek MA. Effect of combination therapy © The Author(s) 2017 consisting of enalapril, alpha-lipoic acid, and menhaden oil on diabetic Nutrition & Diabetes (2017) 1 – 10

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