Metabolic Pathways in the Pathophysiology of Diabetic Retinopathy - Journal of the Foundations of Ophthalmology

Nishant Aggarwal

Background

The WHO estimates 8.5% of the adult population have diabetes. A long-term microvascular complication of diabetes is diabetic retinopathy (DR). Among patients aged 25-74, diabetic retinopathy is the leading cause of vision loss worldwide. By 2023, an estimated 191 million people will have DR of which 56.3 million are expected to have vision-threatening DR (1). Key determinants of the risk of developing DR are the age of the patient, duration of diabetes, and glycaemic control (2). This short article will describe three major metabolic pathways underlying the pathophysiology of DR.

Metabolic pathways

The key contributor to DR is chronic hyperglycaemia. This is backed up by data from the UKPDS (3) and DCCT (4) trials wherein those with better glycaemic control were less likely to develop symptoms. The pathways mentioned below offer an alternative route for glucose metabolism in hyperglycaemia, when occurring in the retina, these pathways underly DR.

Polyol (sorbitol) pathway

This is a two-step metabolic pathway converting glucose to fructose. Glucose is first reduced to sorbitol by the enzyme aldolase reductase, the step utilises a hydrogen group donated by NADPH resulting in NADP+ as byproduct. Subsequently sorbitol is converted into fructose by the enzyme sorbitol dehydrogenase, this donates a hydrogen group to NAD+ releasing a NADH (5).

Importantly, aldolase reductase, which catalyses the conversion of glucose into sorbitol, has a relatively low affinity for glucose and thus this pathway is activated predominantly in states of hyperglycaemia (5). In diabetes, the first step of this reaction will occur excessively in the retina: the issue arises once sorbitol and NADP+ are generated from this reaction. Retinal tissue is deficient in sorbitol dehydrogenase, which catalyses the 2^nd step of this pathway (5). Hence, hyperglycaemia results in the accumulation of sorbitol and reduces the available NADPH in retinal cells. The accumulation of sorbitol draws fluid intracellularly resulting in osmotic damage of retinal vascular cells, RPE cells, and leads to the loss of pericyte cells (6, 7). Lack of NADPH, required by glutathione to chemically reduce damaging oxidative species, makes the retina vulnerable to oxidative stress (8).

Protein Kinase C (PKC) Activation

An increase in glycolysis secondary to hyperglycaemia occurs in vascular and retinal cells. In states of high glycolysis, and intermediate glyceraldehyde-3-phosphate (G-3-P) can accumulate. G-3-P accumulation leads to the synthesis of diacylglycerol (DAG) which subsequently activates protein kinase C (PKC) enzymes (9). PKC enzymes are a family of related isoenzymes which are involved in regulating tissue enzymes, receptor pathway, and transcription factor activation. Increased PKC activity, as noted in the hyperglycaemic state, is known to trigger a cascade a retinal pathophysiological responses (10). PKC activation leads changes in endothelial permeability, blood flow, and the formation of angiogenic growth factors (10-13). These changes contribute towards retinal leakage, ischaemia, and neovascularisation (9).

Advanced glycation end-products (AGEs) formation

The production of advanced glycation end-products (AGEs) is closely related to the hyperglycaemic state. Reducing sugars, without the need for enzymatic catalysation, react with proteins, lipids, and nucleic acids (14). This initial process is called the Maillard reaction and involved the formation of Schiff bases and Amadori products, subsequently these products are converted irreversibly into AGEs (14). Oftentimes, the stable proteins commonly affected by advanced glycation, such as collagen, tend to lead to long-lived heterogenous AGE structures. AGEs are known to form pathological cross-link covalent bonds with proteins present in the retinal cells altering their structure and thereby compromising their function (14, 15). Structures compromised include basement membranes, receptors, and epithelial cells of capillaries. AGEs are also known to interact with RAGEs (receptors for AGEs). After AGE-RAGE binding, in vitro studies have revealed this leads to a cascade of reactions leading to products related to increased oxidative stress and inflammation (16, 17).

Interactions between metabolic pathways have a multiplicative effect on the pathophysiology in DR. The polyol pathway releasing fructose is a key contributor to the production of AGEs, as fructose is to known create AGEs at a much faster rate than glucose (18). In addition, both the polyol and AGE pathway both eventually lead to increased oxidative stress.

Clinical Signs in DR (19)

These three metabolic pathways often work in different ways to intensify the damage on retinal cellular structures. All three pathways lead to endothelial damage which may eventually appear as microaneurysms on examination. Rupture of these microaneurysms leads to the development of dot and blot haemorrhages. Inflammation increases vascular permeability, exacerbating any retinal leakage as the result of endothelial damage. Excess fluid leaking into the retina alongside sediment containing macrophages, lipids and other cellular waste results in diabetic macular oedema and hard exudates. Vascular occlusion may subsequently occur after inflammation-activated leucocytes and AGEs adhere to the damaged vascular endothelial wall. This results in cell ischaemia and the subsequent death and oedema of nerve fibre layers, appearing as the classical fluffy cotton-wool spots. Ischaemia, in conjunction with PKC activation, releases pro-angiogenic VEGF leading to late-stage proliferative DR.

Concluding remarks

These three metabolic pathways: the polyol pathway, PKC activation and AGE formation are crucial in kick-starting and progressing the pathology of DR. Understanding each in depth helps us appreciate the importance of glycaemic control and may reveal future pharmacological therapeutic targets. Each leads to cellular damage, oxidative stress, and inflammation. These changes result in increased vascular permeability and capillary occlusion seen in the retinal vasculature, leading to the classical staged signs of DR.

References

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