Diabetes mellitus (DM) is a major health problem with devastating effects on ocular health in both industrialized and developing countries. To understand the cause of diabetic keratopathy, we investigated innervation and its correlation with delayed corneal epithelial wound healing in type 2 diabetic Goto-Kakizaki (GK) rats. Corneal wounds were prepared by removal of the corneal epithelium and documented using a TRC-50X. ALX injection caused elevated levels of serum glucose in diabetic group. Recently, diabetic keratopathy (DK) and retinopathy (DR) had attracted major power of both clinical and basic researches because of their clinical importance. Alteration of this communication system results in lachrymal hyposecretion of increasing intensity, the seriousness of which may not be perceived by the patient, simply because they are affected by diabetic neurodystrophy of the cornea. A history of nephropathy and/or peripheral neuropathy (all p < 0.001), decreased corneal sensation (all p < or = 0.03), and pathological vibration sensation (p < or = 0.04) were significantly associated with a decrease in NFD, NFL, and NB (except vibration sensation). Systemic application of NTX to the abraded corneas of rats, and topical administration of NTX to the injured rabbit ocular surface, increased re-epithelialization. Diabetic keratopathy comprises several symptomatic corneal conditions inducing superficial punctate keratopathy and persistent corneal epithelial erosion.1 The latter can be encountered especially after vitreoretinal surgery, where oedematous and cloudy corneal epithelium, often manually removed to restore clarity, results postoperatively in a poorly healing corneal epithelial surface. Because of this abnormal composition of the tears, the acidity level of the tears change cause the process to occur even quicker, resulting in band keratopathy. The medial and intimal corneal optical density and central corneal thickness were positively correlated with the course of the disease. Keratopathy in the presence of diabetes should be considered as a potential sight threatening condition and thence must be given appropriate clinical attention and increased research interest. Poor skin elasticity was manifested. Results and discussion: The preformulation studies showed that NTX is a hydrophilic drug with a log P value of 1.61 at 35oC.
Thirteen of the 16 projects have been evaluated in clinical trials. Given the success of ACT1 in dermal indication programs and the positive pre-clinical efficacy outcomes in relation to corneal healing, the objectives of this BrIDGs application are aimed at safety evaluation and optimization of an ACT1 formulation with the goal to complete a pre-clinical safety package for an IND application and pave the way for human clinical evaluation. Fewer nerve fibers were detected compared with Wistar rats. In this issue, the authors have shown that topical ARI treatment was effective in the restoration of corneal epithelial barrier function, but not in the prevention of superficial punctate keratopathy. The patients were allowed to relax in a chair, and were asked to look at a videotape camera placed 3 m away from the patient. Decrease in the corneal sensation23 and loss of nerve derived trophic factor have been postulated as causative factors in the development of diabetic keratopathy. Nakamura et al have revealed that insulin-like growth factor 1 (IGF-1) and substance P, a neuropeptide present in sensory nerves, accelerate corneal epithelial wound healing.24 In addition, the authors showed that topical application of substance P and IGF-1 accelerated the corneal epithelial wound healing process in diabetic animals.
These studies help to strengthen the potential pathogenic link between decreased corneal sensation and diabetic keratopathy. Other putative causes of diabetic keratopathy, in addition to enzymatic and neural dysregulations, include structural abnormalities in the corneal epithelium basement membrane.10,25–27 Kenyon et al were the first to highlight the abnormal interaction of the corneal epithelium and basement membrane.27 They showed that corneal epithelial basement membrane in addition to corneal epithelium was removed with manual epithelial removal during vitreoretinal surgery. For this reason, they speculated that bare corneal stroma, without basement membrane, after corneal epithelial abrasion was the reason for a delay in corneal epithelial wound healing.27 Histologically, thickening and multilamination of the basement membrane25 and a decrease in the penetration of anchoring fibrils (type VII collagen)10 were noted in diabetic corneas. These structural changes of the basement membrane in diabetic cornea may account for the loose attachment of corneal epithelial cells. Advanced glycation end products (AGEs) have been implicated in the development of diabetic keratopathy and maybe at least partly explain some of the structural changes noted.26,28 AGEs are known to deposit in the basement membrane of the corneal epithelial cells of diabetic patients.26 When this happens the molecular structure of basement membrane components changes and they lose adhesive property. In this way, the corneal epithelial cells lose a clue for the attachment on the basement membrane. In addition, aminoguanidine, an antioxidant, was effective in inhibiting AGE formation and thus ameliorated the attachment of corneal epithelial cells to the basement membrane.26 However, the in vivo effect of aminoguanidine on diabetic keratopathy remains unknown.
This review has alluded to several common molecular mechanisms previously implicated in the pathogenesis of systemic diabetic complications, and now also implicated in the pathogenesis of diabetic keratopathy. Potentially, diabetic keratopathy provides a pathogenic mechanistic model to shed light upon complications within other more complex organs. The value of using such a simple model as the cornea to shed light on complications within structurally much more complex organs, has previously already been elegantly demonstrated by investigators such as Gimbrone et al.29 It may now be possible to use this simple organ, the cornea, with all its inherent advantages of accessibility, clarity, ease of observation, and lack of cellular complexity to investigate diabetic pathology secondary to increases in polyol pathway and deposition of AGEs. I think that the potential value of diabetic keratopathy as a simplistic model of diabetic complications cannot be overstated. For this reason, I postulate that the model should be considered for adoption throughout diabetic research laboratories and within institutions performing double blinded clinical studies determining the effect of novel treatments upon systemic diabetic complications. I thank Dr Tetsuro Oshika in the University of Tsukuba, Institute of Clinical Medicines, and Dr Johnny Moore and Dr Tara Moore of the University of Ulster, School of Biomedical Sciences for the preparation of this article.