Beyond Numerical Thresholds: A Systems-Level Perspective on Dysglycaemia and the Liver–Brain Axis in Brain Injury

Glucose is more than an energetic substrate: its homeostasis emerges from continuous interactions between peripheral glucose-regulatory organs and the brain, where glucose availability, sensing, and utilisation must be dynamically matched to metabolic demands. This narrative review examines how disruption of this balance may intersect with oxidative stress, inflammation, and brain vulnerability at the extremes of life. In preterm neonates, the definition of pathological glycaemic states remains heterogeneous, while hypoglycaemia, hyperglycaemia, and particularly glycaemic variability may represent different manifestations of dysglycaemia within an immature homeostatic system. Experimental and clinical evidence links these disturbances, with different degrees of certainty, to oxidative stress, inflammatory responses, adverse neurological outcomes, and white matter vulnerability. The developing brain is particularly susceptible to redox imbalance because of maturation-dependent antioxidant defences and the vulnerability of developing white matter. At the opposite extreme of life, ageing is accompanied by alterations in cerebral glucose and energy metabolism, while neurodegenerative disorders show disturbances in glucose transport and utilisation together with mitochondrial dysfunction, oxidative stress, inflammation, and neuronal and white matter abnormalities. We propose the Biochemical and Physiological Mirror as a conceptual interpretation of these apparently distant conditions: developmental immaturity and age-related decline represent distinct biological trajectories that may converge on partially shared glucose–redox–inflammatory intersections. Within the Crossword Effect, glucose therefore acquires biological meaning not as an isolated concentration but through its context-dependent relationships with metabolic, redox, inflammatory, cellular, and developmental information. Viewing dysglycaemia as a systems-level disturbance rather than solely as deviation from a numerical threshold may provide a more integrated framework for understanding brain vulnerability across the lifespan.