La diabetic retinopathy (RD) is the leading cause of blindness in individuals under 50 years of age with diabetes mellitus, affecting almost 40% of patients.
The main risk factors associated with the early onset and rapid progression of diabetic retinopathy include the duration of diabetes, poor glycaemic control and the concomitant presence of hypertension.
DR is classified into two forms, an early and less severe (non-proliferating) and an advanced (proliferating) form.
In DR, hyperglycaemia damages the structure of blood vessels, predisposing to the formation of microaneurysms, microhaemorrhages and abnormalities of retinal vascular calibre. These abnormalities can lead to the passage of certain blood components through the damaged vessel walls, or to reduced perfusion of the retinal tissue, up to complete ischaemia. The occlusion of retinal capillaries and the subsequent formation of ischaemic retinal areas are the stimulus for the formation of neovases, which characterise the proliferating form.
Diabetic Retinopathy and Inflammation
L'chronic inflammation is largely involved in the development of diabetic retinopathy and its complications. In immunodependent diseases, the inflammatory process induces a complex cascade of biological, molecular and cellular signals that alter the physiological responses of the affected ocular tissues. The inflammatory stimulus due to diabetes can disturb the natural balance of ocular tissues, thus producing an 'inflamed' phenotype. The result of these processes is the increased expression of inflammatory cytokines (IL-1 and TNF), chemotactic proteins (MCP-1), growth factors (TGF-β and VEGF) and apoptotic phenomena, which together contribute to the onset of various ocular diseases.
Evidence of leucocyte activation in DR
In diabetes, the initial site of injury is in the β-cells of the islets of Langerhans, whose cell death causes the release of local and systemic cytokines and chemokines affecting all tissues, including the bone marrow. Therefore, circulating leukocytes derived from the bone marrow are persistently activated in situ and then enter the circulation and tissues. This can occur as early as two weeks after the onset of hyperglycaemia.
Glucose, in fact, can activate blood mononuclear cells because monocytes express on their surface the glucose transporters GLUT 1, 3 and 5, which they use to take up glucose by facilitated diffusion. GLUT 1, in particular, is overexpressed in pro-inflammatory macrophages to support the over-regulation of glycolytic metabolism. High levels of environmental glucose, together with activation due to exposure to cytokines released as a result of tissue damage (such as IL-1b and TNF-a), activate leukocytes to increase glucose uptake and metabolism, mainly through aerobic glycolysis and increased hexokinase (Hx) activity. Hx converts glucose to glucose-6-phosphate in the initial stages of glycolysis and is itself a PAMP that positively regulates leucocyte activation, while glucose sensor pyruvate kinase M2 (PKM2), which normally combines with fructose 1,6-bis-phosphate to complete the production of phospho-enol-pyruvate and pyruvate, is partially converted to the inactive monomer form. The monomeric PKM2 translocates into the nucleus, where it activates factor 1-associated genes𝛂 inducible by hypoxia (HIF-1𝛂), which is necessary for the production of VEGF. Therefore, pro-inflammatory circulating leucocytes activated and trapped in the retinal microcirculation are not only agents of capillary non-perfusion and retinal ischaemia, but are factors that can induce increased vascular permeability (VEGF/VPF) as well as induce local angiogenic responses. Activated leucocytes, in the presence of high glucose levels, also promote inflammation by shunting the accumulation of succinate, while the excess extracellular succinate released acts as a stimulant for further leucocyte activation and recruitment.
Ultimately, glucose and its products comprise a set of metabolites that can induce leukocyte activation; whereas lipid elevation, dyslipidaemia and in particular 'bad' lipids indirectly activate leukocytes through the release of cytokines, as a result of dysregulated sphingolipid metabolism.
The common denominator of this pathology therefore seems to be chronic and dysregulated leucocyte activation, which has widespread effects on tissues in general and the retina in particular.
Mechanism of leucocyte activation
The way in which leukocytes are activated in diabetes is still poorly defined but probably follows a similar pathway to what happens in tissue damage. β-cell damage in type 1 diabetes mellitus leads to the release of IL-1, which then initiates the process of leucocyte activation. Hyperglycaemia from β-cell loss or nutrient overload, combined with dysbiosis, associated with the microbiome and endotoxaemia, may be sufficient to support chronic leucocyte activation. Increased aerobic glycolysis and exokinase activity is likely to contribute to chronic leucocyte activation. Indeed, aerobic glycolysis mediated by mTOR and HIF-1𝛂 underlies the memory of innate immune cells, which may contribute to the ready activation of myeloid cells chronically exposed to metabolic stimuli. More recently, it has been shown that circulating myeloid cells (monocytes/macrophages) in patients with diabetes have elevated levels of pSTAT3, a regulatory molecule of cell signalling, while specific deletion of SOCS3 in the same cells (LysM -SOCS) leads to increased leucostasis and capillary dropout.
Whatever the precise mechanism, chronic inflammation with activated leucocytes and circulating inflammatory mediators is clearly a significant feature of diabetes, present from the onset of the disease and appears to be a direct cause of the characteristic microvascular disease that leads to clinical symptoms such as diabetic retinopathy.
Bibliography:
Dr. Carmelo Chines
Direttore responsabile
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