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

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

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].

In pathological conditions in which a deficiency of IRBP exists, an important anomaly of the photoreceptor cells and the visual cycle can be detected which leads in some cases to the development of retinitis pigmentosa, accumulation of the cytotoxic bis-retinoid A2E, cone-rod pho-

IRBP is linked to an autosomal recessive form of retinitis pigmentosa. A heterozygous T-C transition at the position 3024 [26] and a missense mutation of D1080N [22] have been identified. *In vitro* studies of this mutation have shown that it produces a non-secreted protein that induces

Other studies correlate the presence of *IRBP* gene mutations and the occurrence of high myopia in humans. This myopia was accompanied with retinal dystrophy observed by ocular coherence tomography (OCT) and electroretinography (ERG). The ERG showed a delay and reduction in the amplitude of the waves corresponding to the cone response. The *IRPB* gene mutations were c.3454G > T;p.E1152 and c.1530 T > A;p.Y510 which were predicted to lead to a nonsense mediated decay with a complete loss of IRBP function [21]. These findings correlate with animal studies in which IRBP−/− mice have shown ERG alterations and histological findings affecting cones [25]. This animal model has also shown alterations in eye shape and visual acuity [20].

The relationship between IRBP deficiency and accumulation of the lipofuscin precursor A2E has only be demonstrated experimentally on two different animal models. *IRBP*−/− mice have been shown by HPLC a retinal A2E increase of 2.7-fold [25]. Another study using an animal model with Müller cell dysfunction found a decreased expression of IRBP which was also accompanied

Considering visual cycle components, decreased IRBP expression is one of the most characteristic changes in diabetes. Many studies have evaluated the changes in protein levels and

One study revealed decreased expression of IRBP determined by both qPCR and protein quantification on post-mortem samples of diabetic patients [28]. Another study showed that

IRBP expression and also attempted to explain the reasons for its depletion.

between the IPM and the cells that carry out the visual cycle [14–16].

**2. Pathologies associated with IRBP deficiency**

38 Early Events in Diabetic Retinopathy and Intervention Strategies

endoplasmic reticular (ER) stress [27].

with accumulation of A2E [24].

**3. Diabetes and IRBP levels**

toreceptor dystrophy and an elongated myopic eye shape [20–25].

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 photoreceptors and the impaired visual cycle.

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 M-cones most severely affected [47].

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].
