Metabolic memory and diabetic retinopathy: Legacy of glycemia and possible steps into future

The response of retinal pathology to interventions in diabetic retinopathy (DR) is often independent of the glycated hemoglobin (HbA1c) values at the point of care. This is despite glucose control being one of the strongest risk factors for the development and progression of DR. Previous preclinical and clinical research has indicated metabolic memory, whereby past cumulative glucose exposure may continue to impact DR for a prolonged period. Preclinical studies have evaluated punitive metabolic memory through poor initial control of DM, whereas clinical studies have evaluated protective metabolic memory through good initial control of DM. In this narrative review, we evaluate the preclinical and clinical evidence regarding metabolic memory and discuss how this may form the basis of preventive care for DR by inducing "metabolic amnesia" in people with a history of uncontrolled diabetes in the past. While our review suggested mitochondrial biology may be one such target, research is still far from a possible clinical trial. We discuss the challenges in such research.