**3. Pathophysiology of DME**

#### **3.1 Pathophysiology**

The pathophysiology of DME is multifactorial and has not been clearly and completely defined since it involves various complex pathological processes [29–31]. In health, the retinal circulation is unique in that retinal capillaries are *Current Management of Diabetic Macular Edema DOI: http://dx.doi.org/10.5772/intechopen.100157*

non-fenestrated, and their endothelial cells have tight junctions which do not allow fluid leakage. A lymphatic system does not exist in the retina, but leakage can occur in the presence of retinal pathology, causing edema and swelling [32]. Chronic capillary non-perfusion and retinal ischemia are said to be the primary contributors to DME [33]. Signaling molecules such as insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PGF), angiopoietin, and most importantly, vascular endothelial growth factor (VEGF) all play a role in the subsequent development of diabetic microangiopathy [33].

The trigger for the vascular damage has been convincingly linked to the chronic hyperglycemia present in DM. Vessel damage occurs via the glucose metabolic pathways, which include the Diacylglycerol (DAG)–protein kinase C (PKC) pathway, Advanced glycation end-products (AGE), Polyol (sorbitol) pathway, Hexosamine pathway, and the plasma kallikrein-kinin system (KKS) [34–36]. The blood-retinal barrier (BRB) is an essential structure that regulates normal visual function [31, 37]. It is a physiologic barrier that tightly regulates the balance of electrolytes, protein, solute, and water movement in and out of the retina. It is composed of both an outer and an inner portion [31, 37]. The inner BRB comprises tight junctions between retinal capillary endothelial cells, basement membrane surrounding it, and pericytes outside [31, 37]. The outer BRB tight junctions exist between retinal pigment epithelial cells located between them the fenestrated choriocapillaris and the outer retina [31, 37].

In DME, disruption of the BRB is common, leading to increased vasopermeability associated with vascular leakage, neovascularization, and inflammation [38]. In chronic hyperglycemia, cellular and structural alteration in the BRB is characterized by the breakdown of cell–cell junctions between endothelial cells, pericyte loss, basement membrane thickening, increased deposition of extracellular matrix components, and Muller cell metabolism disturbance heralding the beginning of the microangiopathy [30, 37, 39]. Over time, continued retinal microvasculature damage results in the release of reactive oxygen species and inflammatory mediators and capillary nonperfusion, giving rise to retinal hypoxia and ischemia that drives upregulation of angiogenic factors, such as vascular endothelial growth factor (VEGF) and breakdown of the BRB [29, 39]. The breakdown of the inner BRB then results in the accumulation of plasma proteins such as albumin, which exerts a high oncotic pressure in the neural interstitium, inducing interstitial edema, neural tissue impairment, and ultimately vision loss if there is a delay in treatment or no treatment at all [29, 31, 40].

Patients with DME have elevated vitreous levels of VEGF, Intracellular Adhesion Molecule-1 (ICAM-1), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 compared to nondiabetic patients [41]. VEGF-A mediates angiogenesis by promoting endothelial cell migration, proliferation, and survival [41]. VEGF-A also possesses inflammatory properties through its capacity to mediate microvascular permeability and increase the adhesion of leukocytes. It has been noted to stimulate expression of ICAM-1 and vascular cell adhesion molecule −1 (VCAM-1), thus incorporating the inflammatory cascade, initiating early diabetic retinal leukocyte adhesion, and aiding the development of diabetic vasculopathy [39, 41]. VEGF-A inhibitors have been shown to reduce vascular permeability [30, 31]. Anti-VEGF agents such as Ranibizumab, Aflibercept, and Bevacizumab administered according to various treatment protocols are currently the gold standard for treating center-involving DME [31, 37, 42]. The introduction of intravitreal anti-VEGF therapy has led to notably improved outcomes for some patients with DR/DME [39]. Nevertheless, there are several practical limitations to the treatment with anti-VEGF. They include; cost, need for frequent intravitreal injections, undertreatment, and incomplete response in some patients [39, 43].

#### **3.2 Alternative pathways**

Furthermore, clinical trials have demonstrated that only 33–45% of DME patients on intravitreal anti-VEGF agents showed three lines or more of visual improvement. Other DME patients showed an intermediate response (5–9 letters of improvement) or inadequate response (<5 letters of improvement or worse). Eyes with suboptimal early vision response showed poorer long-term visual outcomes than eyes with pronounced early response [37, 44, 45]. In the clinical setting, available data have shown that anti-VEGF therapy does not live up to the high goals set by clinical trials, leaving patients with suboptimal vision [46]. These limitations have resulted in exploring alternate pathways involved in aberrant angiogenesis, including the Tie-2 pathway and the effect of genetics [39].

The angiopoietin-tyrosine-protein kinase (Ang-Tie) system plays an essential and complementary role alongside VEGF-mediated vessel formation and vascular stability [42]. The angiopoietins, Ang-1 and Ang-2, are a family of growth factors that interact with one another to play a vital role in vessel homeostasis, angiogenesis, and vascular permeability via interacting with the Tie-2 transmembrane receptor tyrosine kinase [37, 39, 42]. Ang-1 plays a protective role in pathological angiogenesis, supports quiescent vessel maturation, and prevents intravesical inflammation [39, 42]. In contrast, Ang-2 promotes vascular instability through its competition with Ang-1 and inhibition of Tie-2, contributing to DME [47]. Ang-2 is upregulated in response to hyperglycemia and plays a vital role in altering the BRB in DME [37]. Increased Ang-2 leads to decreased phosphorylation of Tie-2, which results in increased retinal vascular permeability [37]. Together Ang-2 and VEGF-A have been reported to produce accelerated neovascularization in the developing retina and ischemic retina [39].

#### **3.3 Systemic control**

The UKPDS and FIELD studies concluded that good control of modifiable risk factors of diabetic retinopathy delayed its development and progression [48–51]. Howbeit, findings of the ADVANCE trial came to a contrary conclusion [52]. Moreover, it has been observed in clinical practice that despite prolonged periods of poor control of glycemic and systemic blood pressure in some patients, DR was not observed, contrary to expectations. On the other hand, some other patients would develop DR within a relatively shorter period of diabetes, despite better control [53, 54]. These observations suggest that mechanisms other than hyperglycemia, elevated blood pressure, and hyperlipidemia contributes to the development and progression of DME and diabetic retinopathy in some patients [55]. In addition, disparities in the risk of developing diabetic retinopathy have been noted among patients of different ethnic groups even after correcting for environmental factors, alluding to the fact that genetic factors may play a role in the pathogenesis of diabetic retinopathy [56–59]. This ethnic bias and variable predisposition bring to the fore the consideration of a concept of genetic predisposition to DME and DR in individuals of diverse ethnicity and genetic constitution.

#### **3.4 Genetics of DME and DR**

Gene mapping has been employed to identify novel genetic variants underlying DME and DR. However, only weak associations have resulted [55, 60]. The Genomewide association studies (GWAS) had identified loci of interest MRPL19 and NRXN3 as novel loci with suggestive association with DME and PDR, respectively, which are sight-threatening complications of DR [61]. Although DR-associated genes have yet

to be replicated and confirmed, these early findings represent the initial groundwork and maybe a preview of DR genetics' complexity [55, 60, 62].
