**Interphotoreceptor Retinoid-Binding Protein Implications in Diabetic Retinopathy Implications in Diabetic Retinopathy**

**Interphotoreceptor Retinoid-Binding Protein** 

DOI: 10.5772/intechopen.72835

#### Kevin Bermea Additional information is available at the end of the chapter

Kevin Bermea

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Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72835

#### **Abstract**

The interphotoreceptor retinoid-binding protein (IRBP) is the most abundant protein in the interphotoreceptor matrix (IPM) and its levels decrease beginning in the early stages of diabetes. IRBP participates in the delivery of retinoids between retinal cells to carry out the visual cycle and also protects those retinoids against degradation in the IPM. IRBP deficiency is related to several conditions such as retinitis pigmentosa, cone-rod dystrophy, increased oxidative stress in the photoreceptors, and myopia. Decreased IRBP levels in diabetes could be due to the secretion of inflammatory cytokines and a direct effect of hyperglycemia on the photoreceptors. It is known that prior to the occurrence of vascular changes in diabetic retina, electrophysiological alterations occur on early potentials. Alterations on the photoreceptor outer segments and increased oxidative stress indicate an important affliction of the photoreceptors from early stages. Due to the importance of IRBP in photoreceptor wellness, its decreased levels may be linked to early photoreceptor affection. More studies are required to describe in detail the whole impact that decreased levels of IRBP in diabetes may have.

**Keywords:** interphotoreceptor retinoid-binding protein, IRBP, visual cycle, oxidative stress, ER-stress, light damage, retinitis pigmentosa, cone-rod dystrophy, photoreceptor damage, photoreceptor, S-cones, M-cones, outer segment, diabetes, neurodegeneration

### **1. Introduction**

Typically, the pathological changes described in diabetic retina involve neovascularization and increased blood vessel permeability, a condition known as diabetic retinopathy (DR). Early changes that occur prior to the vascular affection have been acquiring more interest by the scientific community. Retinal proteomic analysis, functional and histopathological studies have revealed alteration in the levels of some proteins and a neurodegeneration state mainly involving ganglion and photoreceptor cells accompanied by reactive gliosis [1–5].

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

The interphotoreceptor retinoid-binding protein (IRBP), which is the most abundant protein in the interphotoreceptor matrix (IPM) [6–10], is one of the principal elements altered in early stages of diabetes. This protein is expressed mainly by the cone and rod photoreceptor cells [11–13]. It binds to the retinoids in the interphotoreceptor matrix and facilitates their exchange between the IPM and the cells that carry out the visual cycle [14–16].

this decreased expression directly correlated with the evolution of the DR, and also tested the effect of glucose and inflammatory cytokines on IRBP expression *in vitro*. They found that high glucose, TNF-α and IL-1β were able to reduce IRBP's expression [29]. A recent study found decreased IRBP levels in diabetic rats and this finding was accompanied by decreased levels of

Interphotoreceptor Retinoid-Binding Protein Implications in Diabetic Retinopathy

http://dx.doi.org/10.5772/intechopen.72835

39

The precise mechanisms responsible for the decreased IRBP levels remain unclear. It is known that high glucose and some circulating fatty acids can induce the secretion of inflammatory cytokines by Müller cells [31, 32]. Despite evidence that high levels of glucose and inflammatory cytokines are able to decrease the expression of IRBP [24, 29], other mechanisms may be involved. With the early onset of diabetes, photoreceptors undergo oxidative stress resulting in increased nitrosative-oxidative stress [33, 34]. This biochemical stress can induce damage to proteins promoting their degradation [35]. The unfolded protein response (UPR) has been detected to be active in photoreceptor cells in animal studies [36]; however no studies have

Disruption of the external limiting membrane (ELM) and the outer retinal barrier (ORB) may play a role in leaking of IRBP into the outer nuclear layer or Bruch's membrane. Studies of animals in diabetic conditions have shown decreased occluding abilities in the Müller cell tight junctions compromising the external limiting membrane [37]. Also retinal pigment epithelium (RPE) dysfunction in early stage diabetes has been described in animal models [38].

Due to its importance on the visual cycle, it is expected that decreased levels of IRBP produce electrophysiological and morphological changes that manifest itself in the damage to the pho-

Deficit of blue-flicker discrimination has been observed in the early stages of diabetes [39]. ERGs have revealed lower oscillatory potential amplitudes suggesting alterations in the photoreceptors and the vision cycle [40–42]. Additionally, color vision has been shown to be altered in these early diabetes stages. Adaptometry studies have also shown alteration in diabetes; even with transient hyperglycemia a patient can have a delay in dark adaptation [43–45].

One study in *Meriones shawi,* an animal model with a human-like macula, after streptozotocininduced diabetes showed alterations in the morphology of the photoreceptor outer segments. Interestingly, the foveal cones appear to be mostly affected revealing a loss of approximately 30% of the M-cones 7 weeks after type 2 diabetes was induced in the animals [46]. Studies in rats also have shown alterations in the photoreceptor outer segments with the S-cones and the

It has been found that glucose levels can influence the vision cycle rhodopsin regeneration ratio [48, 49]. Recently, one research group found depletion of rhodopsin regeneration with an accompanying decrease in STRA6, IRBP, and 11-cis retinal (11-cRAL) in a diabetic animal model [30].

It is still unclear the impact of these mechanisms over the IRBP levels.

**4. Outcomes of IRBP's decreased levels in diabetes**

11-cRAL and rhodopsin synthesis [30].

linked this process to decreased IRBP levels.

toreceptors and the impaired visual cycle.

M-cones most severely affected [47].

Aside from the retinoid delivery, IRBP protects retinoids against degradation [17], the retinal cells from oxidative stress and light-induced injury [18, 19], and is important for eye development [20].
