# Involvement of Vasoactive Intestinal Peptide Family Members in Diabetic Keratopathy
###### Abstract  
Diabetic keratopathy (DK) is a common ocular complication of diabetes, characterized by alteration of the normal wound-healing mechanism, reduction of epithelial hemidessmoomes, disruption of the basement membrane, impaired barrier function, reduced corneal sensitivity, corneal ulcers, and corneal edema. The limited number of clinical studies do not allow a full characterization of the pathophysiology of DK and, until now, effective therapeutic approaches have not been available. However, in recent years, neuropeptides gained great attention for their biochemical characteristics and therapeutic potential. This review focuses on the role of neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the eye and, in particular, in the cornea, in physiological conditions, or during DK, by providing an overview of this diabetes mellitus complication. VIP; PACAP; ADNP; cornea; diabetic keratopathy +
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of the superficial capillary plexus, and deep capillary plexus can be signs of endothelial damage and dysfunction, OCTA could also be a valid modality to detect diabetic-induced abnormalities [9; 10; 11; 12]. Another useful test is in vivo corneal confocal microscopy (IVCCM), a non-invasive and reproducible technique that allows for the study of the living human cornea, including the cellular structure, as well as sub-basal nerve plexus [13; 14]. DK affects 47-64% of patients with DM; therefore, it has a profound social and economic impact. In particular, according to the Italian National Health Service, the mean annual treatment cost of neurotrophic keratopathy per patient is around EUR 5167 in the case of persistent epithelial defect, and EUR 10,885 in the case of corneal ulcer without perforation [15]. The human cornea (Figure 1), forming with the sclera the outermost part of the eye, is mechanically strong and transparent since it exerts barrier and refractive functions. The cornea comprises five different layers: the epithelium, Bowman's layer, Stroma, Descemet's membrane, and endothelium. The epithelium, the outermost layer of the cornea, acts as a barrier by protecting the eye against the external insult. It is formed by four to six layers of nonkeratinized stratified squamous epithelial cells. These cells show different morphology comprising the basal columnar, wing, and superficial squamous cells. The corneal epithelium has high regenerative capacity due to the presence of limbal epithelial stem cells (LESCs), which reside in an annular transition zone known as the limbus, laying at the junction area between the cornea and the sclera. Below the epithelium is the Bowman's membrane (BM), composed of collagen fibrils, which are involved in the cornea's shape [16]. The major part of the cornea thickness is represented by the stroma, whose transparency, avascularity, and strength depend on its accurate composition. In fact, it is formed by extracellular matrix (ECM) molecules, water, and a communicating network of neural crest-derived keratocytes, synthesizing the stromal extracellular matrix [17; 18]. Between the posterior stroma and the corneal endothelial layer, there is Descemet's membrane which is an acellular extracellular matrix composed of hexagonal collagen VIII networks, as well as associated collagens IV and XII [18]. The inner corneal layer is represented by the endothelium, which is formed by a single layer of flat hexagonal cells. Corneal endothelium plays a dual essential role as a barrier and active pump, by regulating the movement of water from the anterior chamber to stroma, thus maintaining its hydration and transparency. Unlike corneal epithelial cells, endothelial cells are not able to regenerate in vivo since they are blocked to the G1 phase of the cell cycle due to cell-cell contact inhibition and a lack of growth factors [19]. Several neuropeptides and relative receptors are largely expressed in the cornea.