High Mobility Group Box Protein (HMGB1): A Potential Therapeutic Target for Diabetic Encephalopathy

HMGB (high mobility group B) is one of the ubiquitous non-histone nuclear protein superfamilies that make up the HMG (high mobility group) protein group. HMGB1 is involved in a variety of physiological and pathological processes in the human body, including a structural role in the cell nucleus as well as replication, repair, DNA transcription, and assembly of nuclear proteins. It functions as a signaling regulator in the cytoplasm and a pro-inflammatory cytokine in the extracellular environment. Among several studies, HMGB1 protein is also emerging as a crucial factor involved in the development and progression of diabetic encephalopathy (DE) along with other factors such as hyperglycaemia-induced oxidative and nitrosative stress. Diabetes' chronic side effect is DE, which manifests as cognitive and psychoneurological dysfunction. The HMGB1 is released outside to the extracellular medium in diabetes condition through active or passive routes, where it functions as a damage-associated molecular pattern (DAMP) molecule to activate several signaling pathways by interacting with receptors for advanced glycosylation end-products (RAGE)/toll like receptors (TLR). HMGB1 reportedly activates inflammatory pathways, disrupts the blood-brain barrier, causes glutamate toxicity and oxidative stress, and promotes neuroinflammation, contributing to the development of cognitive impairment and neuronal damage which is suggestive of the involvement of HMGB1 in the enhancement of the diabetes-induced encephalopathic condition. Additionally, HMGB1 is reported to induce insulin resistance, further exacerbating the metabolic dysfunction associated with diabetes mellitus (DM). Thus, the present review explores the possible pathways associated with DM-induced hyperactivation of HMGB1 ultimately leading to DE.