Novel Insights into the Mechanism and Treatment of Diabetes-Related Brain Complications: Focusing on the Blood-Brain Barrier Impairment

Diabetes mellitus often leads to secondary brain disorders, thus increasing the risk of mortality. The blood-brain barrier (BBB) is a peripheral-central defense mechanism that significantly impacts diabetes-related brain complications. Under hyperglycemic conditions, the BBB undergoes pathological structural alterations, leading to increased permeability and transport dysfunction. Clinically, BBB damage induces diabetes-related brain complications such as cognitive impairment, stroke, and depression. Notably, BBB damage can occur before the onset of disease symptoms in the brain and may serve as a predictor of disease progression and prognosis. Hyperglycemia is the main cause of BBB damage and can induce oxidative stress, inflammatory response, Advanced glycation end products (AGEs) accumulation, and high-mobility group box 1 (HMGB1) signaling axis activation. These factors lead to endothelial dysfunction, disruption of tight junction proteins, loss of pericytes, activation of astrocytes and microglia, disruption of the actin cytoskeleton, alterations in the basement membrane, and an increase in matrix metalloproteinases (MMPs). Collectively, these processes contribute to brain injury in patients with diabetes. Lifestyle interventions and hypoglycemic, antihypertensive, and lipid-lowering agents play therapeutic roles in BBB damage and diabetes-related brain complications. However, the role of some drugs in this context is controversial and remains known only at the animal and cellular levels. Several studies have investigated the therapeutic potential of targeted nanomedicines and natural compounds; however, it remains challenging to translate their research findings to clinical practice. In conclusion, this review highlights the clinical evidence, pathological mechanisms, and existing treatment options for BBB damage in patients with diabetes-related brain complications. It also demonstrates the potential of targeted nanomedicines and natural compounds, providing a foundation for future research.