Sugar for the brain: the role of glucose in physiological and pathological brain function

•We provide a comprehensive overview of the role of glucose metabolism in normal brain function. •We analyze the contribution of glucose metabolism to brain physiology. •We discuss controversies in energy substrate consumption and utilization. •We highlight the connection between glucose metabolism and cell death. •We review the pathophysiological consequences of balanced and disturbed glucose metabolism. The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We synthesize these findings to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation that lead to disease. The mammalian brain depends upon glucose as its main source of energy, and tight regulation of glucose metabolism is critical for brain physiology. Consistent with its critical role for physiological brain function, disruption of normal glucose metabolism as well as its interdependence with cell death pathways forms the pathophysiological basis for many brain disorders. Here, we review recent advances in understanding how glucose metabolism sustains basic brain physiology. We synthesize these findings to form a comprehensive picture of the cooperation required between different systems and cell types, and the specific breakdowns in this cooperation that lead to disease. an intracellular ‘recycling’ pathway that can be activated under conditions of metabolic stress to inhibit cell death. It involves the lysosomal degradation of cytoplasmic proteins or entire organelles for catabolic regeneration of nutrient pools [61Kroemer G. et al.Autophagy and the integrated stress response.Mol. Cell. 2010; 40: 280-293Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar]. the permeability barrier arising from tight junctions between brain endothelial cells, restricting diffusion from blood to brain. Entry into the brain is limited to molecules that can diffuse across membranes (e.g., oxygen and other gases, or lipid-permeable compounds) or have transporter molecules (e.g., glucose transporters). Neuroactive compounds (e.g., glutamate or adrenalin) in the blood are restricted from entering into the brain. a response by the brain to a specific stimulus (e.g., sensory stimulation) that increases cellular activity and metabolism above the ‘resting’ and/or baseline value before onset of the stimulus. Brain activation has the same meaning but is a more general term that includes increased activity during abnormal or disease states. the release of the neurotransmitter glutamate from excitatory neurons, its sodium-dependent uptake by astrocytes, its conversion to glutamine by glutamine synthetase in astrocytes, the release of glutamine and uptake into neurons followed by the conversion to glutamate by glutaminase and its repackaging into synaptic vesicles. a glycolytic enzyme that reduces NAD+ to NADH and converts D-glyceraldehyde-3-phosphate to 1,3-bisphospho-D-glycerate, an intermediary metabolite in the generation of pyruvate. a cytoplasmic pathway for metabolism of one molecule of glucose to produce two molecules of pyruvate, with phosphorylation of 2 ADP to form 2 ATP and reduction of 2 NAD+ to 2 NADH. Cytoplasmic oxidation of NADH can be achieved by conversion of pyruvate to lactate by the LDH reaction or via the MAS (see Figure 2A in main text). The MAS is required to generate pyruvate for oxidation in the TCA cycle, whereas LDH removes this substrate from the cell. Net production of lactate in the presence of adequate levels and delivery of oxygen is sometimes termed ‘aerobic’ glycolysis, contrasting the massive production of lactate under hypoxia or anoxia (‘anaerobic’ glycolysis). the enzyme catalyzing the first step in glucose metabolism: the irreversible conversion of glucose to Glc-6-P in an ATP-dependent reaction. The brain has different HK isoforms that have specific functions. HKI is the major isoform in brain for the glycolytic pathway; it has a broad substrate specificity and is feedback-inhibited by Glc-6-P. HKII is a minor, hypoxia-regulated isoform in the brain that controls neuronal survival depending on the metabolic state. HKIV (glucokinase, GK) is a minor isoform of hexokinase in the brain that has an important role in glucose-sensing neurons; it is specific for glucose and is not inhibited by Glc-6-P. a diet that has a high fat and low carbohydrate content so that plasma levels of ketone bodies (acetoacetate and β-hydroxybutyrate) increase and serve as alternative oxidative fuel. a synergistic interaction between different cells or cell types in which compounds produced in one cell are used by another cell. groups of neurons, astrocytes, endothelial cells, vascular smooth muscle cells, and pericytes that are involved in local signaling activities, metabolic interactions, and regulation of blood flow. a mitochondrial pathway for oxidation of pyruvate to produce 3 CO2 and generate FADH2 and NADH that are oxidized via the electron transport chain with conversion of oxygen to water and formation of approximately 32 ATP per glucose molecule. This ATP yield is less than the theoretical maximum due to proton leakage across the mitochondrial membrane.