Diabetes mellitus is a group of diseases characterized by chronic hyperglycemia, and the most common expressions of this condition are type 1, type 2, and gestational diabetes
[1]. While type 1 diabetes is an autoimmune disease causing an abnormal immune response against insulin-producing
β-cells, significantly blunting the expression of this hormone
[2], type 2
[3] and gestational diabetes
[4] are also characterized by a certain level of skeletal muscle, liver, and adipose tissue insulin resistance. Genetic, environmental, and behavioral factors, as well as maternal obesity, can cause these conditions. Diabetes incidence is increasing worldwide
[5]: the population affected by this disease triplicated in the last 40 years
[6], and it keeps on growing
[7]. Diabetes-associated conditions affect multiple organs and organ systems, resulting in polyneuropathy
[8], angiopathy
[9], infections
[10], nephropathy
[10], dementia
[11], cardiovascular complications
[12], lower limb amputation
[13], and blindness
[14]. These phenomena are often irreversible and accompanied by a structural and functional impairment of the tissue microcirculation
[15]. Vascular degeneration is particularly prominent in the eye, leading to diabetic retinopathy (DR)
[16]. DR affects patients aged between 20 and 65
[17], and its symptoms appear about ten years after diabetes onset
[18]. It has been estimated that 20–30 million patients are at risk of irreversible vision loss because of DR
[19][20], which is currently one of the leading causes of visual impairment (
Figure 1)
[21][22][23] and the leading cause of blindness in preventable retinal diseases
[24].
DR is caused by a significant retinal and choroidal capillary network degeneration, due to a local chronic inflammation sustained by advanced-glycation end-products (AGEs)
[25], reactive oxygen species (ROS)
[26], growth factors, and interleukins
[27][28].
In DR, the blood–retinal barrier (BRB) becomes highly permeable, causing local edema, necrosis, and ischemic phenomena
[29]. The BRB function depends on the integrity and proper conformation of endothelial intercellular junction complexes that are already significantly affected during the first phases of DR. A high vascular endothelial growth factor (VEGF) pathway activity
[30] and a misbalance in ROS generation and elimination
[31][32][33] induce junction disassembly and leaky blood capillary formation
[34]. These phenomena can also affect the protein composition of the vitreous humor
[35].
To re-establish the normal tissue vascular flow, a neo-angiogenesis process driven by VEGF expression occurs in the retinal and choroidal tissue
[36], potentially causing retinal detachment and vision loss
[37].