# Involvement of Vasoactive Intestinal Peptide Family Members in Diabetic Keratopathy
## 3 Expression of Neuropeptides in the Cornea
### Vasoactive Intestinal Peptide (VIP)  
VIP is a 28-amino-acid peptide first isolated from the duodenums of pigs by [PERSON] and [PERSON] in 1970 [65]. It belongs to the secretin/glucagon family of peptide hormones, sharing 70% sequence identity with the neuropeptide PACAP. VIP is secreted by neurons, endocrine, and immune cells, and it is largely distributed throughout the central nervous system (CNS), peripheral nervous system (PNS), and peripheral organs and tissues, including heart, eye, lung, thyroid, kidney, urinary and gastrointestinal tracts, genital organs, and the immune system [66] (Figure 2). \begin{table}
\begin{tabular}{c c c c} \hline
**Neuropeptide** & **Abbreviation** & **Corneal Distribution** & **References** \\ \hline Vasoactive intestinal & VIP & Nerve endings; endothelium & [45; 47; 48; 49] \\  peptide & & & \\ \hline Pituitary adenylate & & Nerve endings; & \\ cyclase-activating & & & \\ polypeptide & & & \\ \hline Activity-dependent & & & \\ Neuroprotective Protein & & & \\ \hline Substance P & SP & Epithelium; stroma & [52; 53; 54] \\ \hline Calictonin gene-related & & & \\ peptide & & & \\ \hline Adrenomedullin & ADM & Nerve endings & [56] \\ \hline Neuropeptide Y & NPY & & \\ \hline Somatostatin & SST & Whole cornea & [58] \\ \hline Alpha & & & \\ melanocyte-stimulating & \(\alpha\)-MSH & Whole cornea & [59] \\ hormone & & & \\ \hline Galanin & GALP & & \\  & & & \\ \hline Neuroensin & NT & & \\ \hline Brain natriuretic peptide & BNP & Epithelium & [57] \\ \hline Nerve growth factor & NGF & Epithelium & [62] \\ \hline Opioid growth factor & & & \\ (OGF)/met-enkephalin & & & \\ \hline \end{tabular}
\end{table} 
Table 1: Neuropeptides expressed in the cornea. Figure 2: Tissue distribution of VIP. Boxplot of transcripts per million (TPM) showing the bulk tissue gene expression for VIP. The Genotype-tissue Expression (GTEx) Portal on 25 October 2023. The mechanism of action of VIP implicates the activation of two subtypes of receptors, VPAC1 and VPAC2, which bind with the same affinity as the other neuropeptide PACAP. VPAC1 and VPAC2 receptors are mainly coupled to the G-protein Gs, stimulating cellular AC activity [67; 68]. The two specific receptors for VIP are largely expressed throughout the human body, including the pancreatic islets, where the VPAC1 receptor regulates glucagon secretion and hepatic glucose production, whereas the VPAC2 receptor improves glucose tolerance through the stimulation of insulin secretion [69; 70; 71; 72]. These data suggest that VPAC1 and VPAC2 receptors can potentially be targeted for the treatment of type 2 diabetes. VIP exerts different biological functions, as a neuromodulator, neurotransmitter, and vasodilator [73; 74; 75]. It regulates smooth muscle activity, epithelial cell secretion, and blood flow in the gastrointestinal tract [65; 76]. VIP is also involved in neurological diseases [77] and in different types of cancers, where it can have a stimulatory or inhibitory role in the growth of neoplastic cells [78; 79; 80; 81]. VIP is also involved in immunomododulation and inflammation by regulating the immunogenic/mature conventional dendritic cells phenotype [82; 83]. In the ocular system, VIP and its receptors are distributed in the retina [84; 85], showing a protective role in ischemic retinal degeneration [86; 87] and in diabetic retinopathy [88; 89; 90; 91]. VIP is also produced at the ocular surface and contributes to the immunosuppressive activity of normal aqueous humor [92]. The peptide is normally present in the tears of healthy subjects, and its levels increased after conjunctival allergen challenge in allergic patients. These data suggest that the local release of VIP can act directly on the epithelia, blood vessels, and immune cells, exerting protective and inflammatory responses [93]. VPAC1 and VPAC2 receptor expression was found at high-intensity levels in the epithelium and stroma of the rabbit cornea [8]. Moreover, in the cornea after _P.