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Maugeri, G.; D’amico, A.G.; Magrì, B.; D’agata, V. Vasoactive Intestinal Peptide Family Members in Diabetic Keratopathy. Encyclopedia. Available online: https://encyclopedia.pub/entry/55521 (accessed on 16 April 2024).
Maugeri G, D’amico AG, Magrì B, D’agata V. Vasoactive Intestinal Peptide Family Members in Diabetic Keratopathy. Encyclopedia. Available at: https://encyclopedia.pub/entry/55521. Accessed April 16, 2024.
Maugeri, Grazia, Agata Grazia D’amico, Benedetta Magrì, Velia D’agata. "Vasoactive Intestinal Peptide Family Members in Diabetic Keratopathy" Encyclopedia, https://encyclopedia.pub/entry/55521 (accessed April 16, 2024).
Maugeri, G., D’amico, A.G., Magrì, B., & D’agata, V. (2024, February 27). Vasoactive Intestinal Peptide Family Members in Diabetic Keratopathy. In Encyclopedia. https://encyclopedia.pub/entry/55521
Maugeri, Grazia, et al. "Vasoactive Intestinal Peptide Family Members in Diabetic Keratopathy." Encyclopedia. Web. 27 February, 2024.
Vasoactive Intestinal Peptide Family Members in Diabetic Keratopathy
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Diabetic keratopathy (DK) is a common ocular complication of diabetes, characterized by alteration of the normal wound-healing mechanism, reduction of epithelial hemidesmosomes, disruption of the basement membrane, impaired barrier function, reduced corneal sensitivity, corneal ulcers, and corneal edema.

VIP PACAP ADNP cornea diabetic keratopathy

1. Introduction

Diabetes mellitus (DM) is an endemic disease occurring all over the world, which is characterized by chronic hyperglycemia. It is caused by total or relative absence in insulin secretion and/or insulin action by the pancreatic β cells [1]. According to the International Diabetes Federation, 537 million adults (20–79 years) are living with diabetes, and this number is predicted to rise to 643 million by 2030 and 783 million by 2045, resulting in a huge health burden on society.
Chronic hyperglycemia gradually induces several complications affecting almost every organ system, including the ocular tissues [2]. Diabetic retinopathy (DR) is the most common ophthalmic complication of DM. However, corneal abnormalities (diabetic keratopathy) are also common in patients with DM and determine the increased morbidity of these patients [3]. Although the relationship between DR and DK is not fully characterized, a decrease in corneal sensitivity is known to affect both insulin-dependent and non-insulin-dependent diabetic patients [4]. Moreover, corneal sensitivity is lower in diabetic as compared to non-diabetic eyes, and it is lower in patients with DR as compared to no DR. Moreover, corneal sensitivity is more altered with the progression of DR [5] and particularly impaired in eyes with proliferative DR as compared to non-proliferative DR [4]. Different instrumental tests can be used to visualize the severity of DK and DR, as well as choroidal damage. Among them, digital retinal fundus image analysis can detect early DR, although it has been shown to have a low negative predictive value [6][7]. Optical Coherence Tomography (OCT) is a non-invasive test to acquire bidimensional images of the different retinal layers, and optical coherence tomography angiography (OCTA) is a novel diagnostic tool to observe the microvasculature of the retina and choroid without the need for dye injection [8]. Since changes in choroidal thickness, retinal thickness, vessel density 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].
Figure 1. Schematic showing pathogenesis of DK. Effects triggered by hyperglycemia in different parts of the cornea result in three main types of dysfunctions characterizing DK: epitheliopathy, neuropathy, and endotheliopathy.

2. Overview of Diabetic Keratopathy

Chronic exposure to hyperglycemia triggers pathophysiological changes in cells, tissues, and organ systems, due to the promotion of oxidative stress, the activation of polyol pathway and protein kinase C (PKC), the formation of advanced glycation end-products (AGEs), and alteration of gene expressions [20]. The cornea is an avascular structure containing no blood vessels, receiving glucose via trans-corneal transport from the aqueous humor. Glucose is also present in tears, but its levels are lower than in the aqueous humor and serum [21]. Given that the cornea receives glucose from the aqueous and not the adjacent tear film, it is not surprising that in patients with diabetes, the cornea is exposed to high levels of oxidative stress and inflammation representing distinct features of diabetes in all other tissues [22][23]. Corneal complications range from mild to severe manifestations and comprise epithelial defects, corneal thickness, erosions, and corneal nerve abnormalities [24] (Figure 1).
Corneal epithelial alterations observed in patients with DM include epithelial fragility, non-healing corneal ulcers, and superficial punctate keratitis (SPK). The latter is characterized by scattered areas of punctate corneal epithelial loss causing photophobia, foreign body sensation, tearing, redness, irritation, and reduced visual acuity [25]. The reduction of corneal epithelial density and thickness is due to the imbalance between cell proliferation, differentiation, migration, and death. Moreover, the accumulation of AGEs counteracts the effective migration of epithelial cells essential for wound healing, leading to recurrent erosions [26]. The impairment of corneal epithelium is closely linked to the increase in glycosylated hemoglobin levels [27], and corneal epithelium barrier alterations expose patients to a higher risk of developing ocular infections than healthy people [28]. Moreover, cataract and laser-assisted in situ keratomileusis (LASIK) surgeries are some of the high-risk interventions for patients with DM, since corneal damage after or during surgery may lead to slow healing and thus frequent corneal erosion damage [29][30]. DK is also characterized by a loss of corneal sensitivity, which could be used by clinicians for the early diagnosis of diabetic peripheral neuropathy and/or DK [31]. In fact, corneal epithelium represents the most innervated and sensible epithelial surface of the human body. In particular, it is innervated by free nerve endings of the ophthalmic division of the trigeminal nerve (cranial nerve V) [32], and corneal nerves are responsible for the sensations of pain from mechanical, thermal, and chemical stimulation [33]. Furthermore, corneal nerves regulate tear secretion and via the regulation of neurotrophic factors maintain ocular surface homeostasis, corneal sensitivity, epithelial health, and wound healing [34][35]. Recent studies showed that, in patients with DM, the density of corneal nerve fiber and branch and the corneal nerve fiber length are significantly reduced. Furthermore, 17% of these patients undergo the loss of 6% or more of corneal nerve fibers per year [36][37][38]. The stroma also shows structural alterations in patients with diabetes, due to the accumulation of AGEs, which provokes non-enzymatic cross-linking between collagen molecules and proteoglycans, thus causing the cornea to stiffen and thicken [39]. Changes in diabetic corneas were also found in corneal endothelial cells, whose density was decreased in patients with diabetes as compared to healthy subjects [30][40]. Accordingly, a recent study involving 120 patients with diabetes and 120 healthy patients demonstrated that hyperglycemia altered corneal endothelium (counts, morphology, and structure) as well as corneal thickness.
Available treatment options for patients affected by DK comprise the use of topical lubricants and antibiotic ointments to increase corneal surface lubrication and prevent infections. However, many potential therapeutic agents such as neuropeptides, growth factors, or cytokines could be used to promote the normalization and regeneration of the impaired human corneal epithelium [25][41].

3. Expression of Neuropeptides in the Cornea

Neuropeptides are signaling molecules of 3 to 100 amino acids that exert key roles in different physiological processes, such as reproduction, body weight regulation, pain, memory, sleep/wake cycles, long-lasting modulation of synaptic transmission, inflammation, tissue repair, and glucose metabolism [42][43]. They exert their functions through the activation of G protein-coupled receptors (GPCRs), which are integral membrane glycoproteins containing seven transmembrane domains [44]. GPCRs are coupled with intracellular heterotrimeric G proteins, which consist of three subunits, the α, β, and γ subunits. Upon receptor activation, the G protein is activated and the α subunit separates from the βγ dimer, and then both α and βγ can modulate the activity of target effectors.
G proteins are classified according to the activity of the Gα subunit as either Gs, Gi/o, or Gq/11 [43]:
  • Gs signaling is involved in adenylyl cyclase (AC) activity, which regulates intracellular adenosine 3′,5′-cyclic monophosphate (cAMP). cAMP is an intracellular signal transmitter that, in turn, acts as a second messenger and activator of cAMP-dependent protein kinase A (PKA).
  • Gi/o signaling is involved in the inhibition of AC activity, resulting in decreased intracellular cAMP production.
  • Gq/11 signaling activates phospholipase Cβ (PLCβ), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2), releasing diacylglycerol (DAG) and 1,4,5-inositol trisphosphate (IP3). DAG activates protein kinase C (PKC), whereas IP3 diffuses to the endoplasmic reticulum (ER) and binds to IP3 receptors on ligand-gated calcium channels on the surface of ER leading to the release of calcium ions.
Neuropeptides are largely synthesized and secreted in the central and peripheral nervous system, as well as in other organs and tissue, including the cornea. Corneal nerves produce various neuropeptides, displayed in Table 1, that play neuromodulatory functions in the healthy and diseased cornea.
Table 1. Neuropeptides expressed in the cornea.

Neuropeptide

Abbreviation

Corneal Distribution

References

Vasoactive intestinal peptide

VIP

Nerve endings; endothelium

[43][45][46][47]

Pituitary adenylate cyclase-activating polypeptide

PACAP

Nerve endings; stroma

[48]

Activity-dependent Neuroprotective Protein

ADNP

Epithelium; stroma

[49]

Substance P

SP

Epithelium; stroma

[50][51][52]

Calcitonin gene-related peptide

CGRP

Nerve endings

[53]

Adrenomedullin

ADM

Nerve endings

[54]

Neuropeptide Y

NPY

Stroma

[55]

Somatostatin

SST

Whole cornea

[56]

Alpha melanocyte-stimulating hormone

α-MSH

Whole cornea

[57]

Galanin

GALP

Epithelium, stroma, and endothelium

[55][58]

Neurotensin

NT

Stroma

[55][59]

Brain natriuretic peptide

BNP

Epithelium

[55]

Nerve growth factor

NGF

Epithelium

[60]

Opioid growth factor (OGF)/met-enkephalin

OGF/MENK

Epithelium

[61][62]

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