Diabetic retinopathy: why some eyes suffer more – a focus on retina-specific risk factors and metabolic memory

Diabetic retinopathy (DR) is a significant microvascular complication of diabetes mellitus (DM) and remains the primary cause of vision loss among diabetic patients, imposing a severe burden on both quality of life and socioeconomic resources. Although hyperglycemia is established as the central driver for the onset and progression of DR, substantial heterogeneity in individual susceptibility exists, as not all patients with comparable diabetic status develop DR. This highlights the influence of additional specific modifying factors. Therefore, systematically elucidating the hierarchical framework of risk factors for DR, with particular emphasis on retina-specific mechanisms and the concept of “metabolic memory,” is crucial for achieving effective clinical risk stratification and formulating individualized prevention and management strategies. This review is based on a systematic analysis of relevant clinical studies from over 20 countries published in the past five years. We synthesized the available evidence to construct a hierarchical framework of risk factors influencing DR development and summarized the key factors. The core driving role of DM and persistent hyperglycemia was first affirmed. We then elaborated on how multilayered modifying factors—encompassing genetic background, comorbid disease history, individual lifestyle choices, and alterations in physical/chemical indicators—synergistically or independently modulate DR risk and progression. Special attention was given to discussing the profound impact of “metabolic memory,” genetic susceptibility, and the unique role of the local retinal microenvironment. This review systematically confirms that DM and its persistent hyperglycemia constitute the indisputable initiator and pathological cornerstone of DR. Upon this foundation, a complex modifying network—formed by genetic predisposition, comorbidities (e.g., nephropathy, hypertension), individual lifestyle, inflammatory and metabolic disturbances, and the specificity of the retinal microenvironment—collectively and differentially regulates disease progression. Comprehending this hierarchical risk system, particularly acknowledging the long-term impact of early intensive glycemic control (“metabolic memory”) and the role of retina-specific pathways, is fundamental to enabling effective clinical risk stratification, early identification of high-risk individuals, and implementing multidisciplinary, precise interventions. Future research should further explore retina-specific metabolic, immune, and genetic mechanisms to propel the development of novel strategies for DR prevention and treatment.