Glycolytic enzyme hexokinase-2 and brain disorders

Recent research suggests increased glucose metabolism in the central nervous system in hyperglycemia occurs in cells expressing hexokinase-2 (astroglia and vascular cells). 

Hexokinase-2-linked glycolytic overload is proposed in explanation for related cell dysfunction driving increased risk of mild cognitive impairment and dementia, Parkinson’s disease, and stroke in patients with diabetes.

This engages mitochondrial dysfunction, protein O-linked β-Nacetylglucosaminylation, protein kinase C, and methylglyoxal induced unfolded protein response and NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome activation—including a vicious cycle of β-amyloid-linked hexokinase-2 expression in microglial cells and brain insulin resistance.

A strategy for prevention is activation of transcription factor nuclear factor erythroid 2-related factor 2 where a candidate intervention (GlucoRegulate) with existing clinical evidence for improving insulin resistance is proposed.

https://www.cell.com/trends/endocrinology-metabolism/fulltext/S1043-2760(26)00245-6

https://sciencemission.com/Hexokinase-2%E2%80%93glycolytic-overload