**Abstract**

Diabetic retinopathy is a prototypical microvascular disorder. Hyperglycemia causes a multiple pathological changes in the retinal vasculature. It has been suggested that apoptosis of pericytes due to high glucose levels plays a key role in the development of the earliest events during diabetic retinopathy. Advancement of the disease resulted in a progressive vessel leakage leading to edematous distortion of macula and increase in hypoxia inducing development of neovascularization with sight threatening complications. Four basis hypotheses explaining the hyperglycemia harmful effects were suggested: (1) increased glucose flux through the aldose reductase pathway, (2) overproduction of advanced glycation end products, (3) activation of protein kinase C isoforms, and (4) increased glucose flux via the hexosamine pathway. It was admitted as well that apoptosis of neurons and glial cell activation occur even earlier than vascular damage. Disturbance in glial cell functions leads to increase in metabolic abnormalities such as glutamate accumulation, promotion of inflammation, and oxidative stress resulting in neuron apoptosis and deterioration of vascular disorders. Clarification of significant biochemical mechanisms involving in the development of diabetic retinopathy can help to create new effective ways in diabetic retinopathy treatment.

**Keywords:** diabetic retinopathy, diabetic maculopathy, microvascular changes, metabolic pathways

#### **1. Introduction**

Diabetic retinopathy (DR) is a common complication of diabetes. Elevated blood glucose levels induce alterations in a number of metabolic pathways that trigger microvascular lesions. It can cause significant vision deterioration due to development of macular edema or proliferative DR leading to intravitreal hemorrhages and tractional retinal detachment. Elaboration of effective methods in the treatment of DR is based on understanding of pathogenesis of this disease.

#### **2. Blood flow changes**

A hallmark of diabetes is a high blood glucose levels. It was shown in nondiabetic animals that infusion of glucose causes a rapid increase of retinal blood flow [1]. Patients with mild or no DR demonstrated significantly increased retinal blood volume flow compared with nondiabetic participants [2, 3]. Apparently, blood flow abnormalities contribute to the pathogenesis of DR and precede the earliest visible signs of diabetic retinal complications. Blood flow in the retina is controlled

mostly by metabolic autoregulation. Metabolic autoregulation is an adaptation of the diameter of vessels to the metabolic demands in the tissues. Oxygen saturation is a principal metabolic stimulus for blood flow changes in the retina. Impaired metabolic autoregulation in patients with DR may be due to changes in the retinal metabolism. It was founded that glucose flux through the polyol pathway in DR disrupts balance between pyruvate and lactate levels that resulted in pseudohypoxia and increased blood flow [4]. Probably, this is a direct mechanism of glucoseinduced hyperperfusion in DR [5]. It was shown that increased blood flow induces increase in shear stress followed by a damage of the endothelial cell lining and basement membrane thickening [6]. Production of the vasoconstrictor endothelin-1 (ET-1) by endothelial cells is changed depending on the level and duration of the shear stress [7]. At the same time increased shear stress stimulates production of vasodilators, namely prostacyclin (PGI2) and nitric oxide (NO) followed by additional increase in blood flow [8, 9]. Hyperglycemia by its direct deleterious effect on pericytes inhibits contraction of small vessels, impairing autoregulation [10]. The dilatation of retinal vessels during the early stages of DR is accompanied with impaired pressure autoregulation. Pressure autoregulation is a capacity of the resistance vessels to adjust diameter to maintain stable microcirculation during changes in the arterial blood pressure. Thereby, in DR the systemic blood pressure more easily conveys to the capillary bed, increasing tangential stress on the capillary wall where it contributes to the formation of microaneurysms, hemorrhages, and breakdown of the blood-retina barrier (BRB) [6, 11]. The fact that hyperperfusion is essential in the development of DR is confirmed by conditions that are associated with its progression and characterized by increased blood flow. Hypertension is an important risk factor for the incidence and progression of DR [12–14]. Pregnancy in patients with diabetes is often associated with a deterioration in DR [15].
