Diabetic retinopathy (DR) is one of the leading causes of blindness among the working-age population worldwide. Traditionally regarded as a typical microvascular disease, a growing body of research clearly demonstrates that retinal metabolic damage is not a passive accompaniment but a causal origin driving neurovascular destruction.
At the 27th Annual Conference of the Chinese Society of Diabetes (CDS 2025), held from November 19 to 22, 2025, Professor Chen Yanming of the Third Affiliated Hospital of Sun Yat-sen University delivered an in-depth presentation on the theme Early Pathological Changes in Diabetic Retinopathy: Metabolic Damage.
Approximately one-third of patients with diabetes globally develop DR. In China, around 19.5 million individuals with diabetes have DR, of whom about one-fifth suffer from vision-threatening forms, making it a leading cause of blindness in the working-age population. Between 1990 and 2020, among the top five global causes of blindness, only DR showed a continuously rising prevalence.
Early DR is characterized mainly by microvascular lesions and impaired neurovascular coupling. Diabetes significantly damages the retinal neurovascular unit, disrupting the interdependent functions of vascular, neural, glial, and immune cells. Specific pathological changes include neuronal injury, immune cell activation, and vascular dysfunction. Collectively, these alterations lead to neurovascular uncoupling, followed by breakdown of the blood–retinal barrier and dysregulated retinal blood flow. Overall, metabolic abnormalities trigger injury to the neurovascular unit and drive the development of microvascular disease, representing the core mechanism underlying early DR pathogenesis.
Mendelian randomization (MR) studies use genetic variants as instrumental variables to infer causal relationships between exposure factors (e.g., lifestyle, metabolic traits) and disease outcomes via the natural random allocation of alleles. Results indicate:
Glucotoxicity: HbA1c shows a significant causal association with all stages of DR, including proliferative diabetic retinopathy (PDR).
Lipotoxicity: High-density lipoprotein cholesterol (HDL‑C) and apolipoprotein A (ApoA) exert significant protective effects against DR progression.
Systemic injury: Alanine transaminase (ALT) is causally linked to DR.Under metabolic stress, high glucose promotes oxidative stress and enhanced inflammation through multiple pathways — including the polyol pathway, protein kinase C (PKC) activation, the hexosamine shunt, and accumulation of advanced glycation end products (AGEs) — thereby inducing endothelial damage, increased vascular permeability, and pericyte apoptosis, forming the classic molecular pathological framework of DR. Concurrently, metabolic reprogramming shifts retinal cells from oxidative phosphorylation to abnormal glycolysis, resulting in inefficient energy supply accompanied by lactate accumulation, further exacerbating inflammatory signaling and neural dysfunction. The retina is not merely an energy-consuming tissue but a hub of metabolism and inflammation, reflecting the metabolic-inflammatory nature of DR.
Furthermore, certain metabolites exert dual roles in DR:
Ceramides, as lipotoxic mediators, are significantly elevated in the vitreous humor of DR patients. They activate inflammation, induce endothelial apoptosis, and disrupt the blood–retinal barrier; targeted blockade markedly reduces retinal vascular leakage and inflammation in mouse models.
Tryptophan and its metabolite indole‑3‑propionic acid (IPA) exhibit anti-inflammatory and neuroprotective effects. Serum levels are significantly decreased in DR patients, and IPA supplementation ameliorates high glucose‑induced retinal inflammation.Research by Professor Chen Yanming’s team reveals that cellular communication network factor 1 (CCN1) is significantly upregulated in DR. It recruits neutrophils to cause vascular leakage, triggering retinal endothelial inflammation and altered capillary function. Dysregulated glucose and lipid metabolism activates the STING pathway in retinal blood vessels, further promoting inflammation.