We highlight the multifaceted role and complex regulation of glucose metabolism in the CNS as well as the physiological and pathophysiological consequences of balanced and disturbed glucose metabolism ( Figure 1). Thus, disruption of pathways of glucose delivery and metabolism leads to debilitating brain diseases.

Glucose metabolism is connected to cell death pathways by glucose-metabolizing enzymes. Cellular compartmentation of glucose transport and metabolism is intimately related to local regulation of blood flow, and glucose-sensing neurons govern the brain-body nutrient axis. Glucose is required to provide the precursors for neurotransmitter synthesis and the ATP to fuel their actions as well as the brain’s energy demands not related to signaling. To this end, we review the bioenergetics of neurotransmission, the cellular composition of a metabolic network, the regulation of cerebral blood flow (CBF), how peripheral glucose metabolism and energy homeostasis are sensed and controlled by the CNS, and the tight regulation of cellular survival through glucose-metabolizing enzymes. It is beyond the scope of this review to resolve these controversies rather it is our aim to highlight conflicting concepts and results to stimulate discussion in key areas. Although brain energy metabolism has been investigated for decades, certain aspects remain controversial, in particular in the field of energy substrate consumption and utilization. Here, we provide a comprehensive overview of the functional implications and recent advances in understanding the fundamental role of glucose metabolism in physiological and pathological brain function. Therefore, tight regulation of glucose metabolism is critical for brain physiology and disturbed glucose metabolism in the brain underlies several diseases affecting both the brain itself as well as the entire organism.

Glucose metabolism provides the fuel for physiological brain function through the generation of ATP, the foundation for neuronal and non-neuronal cellular maintenance, as well as the generation of neurotransmitters.

In humans, the brain accounts for ~2% of the body weight, but it consumes ~20% of glucose-derived energy making it the main consumer of glucose (~5.6 mg glucose per 100 g human brain tissue per minute ). In the adult brain, neurons have the highest energy demand, requiring continuous delivery of glucose from blood. The mammalian brain depends on glucose as its main source of energy.

Are neurons only in the brain