Brain glucose metabolism

The brain is an obligate glucose consumer, although it can utilize other metabolites in special situations such as fasting. It has very high energy consumption for its size, mainly due to the energy expenditure needed to maintain the potential difference across nerve cell membranes, as well as axonal and dendritic transport and tissue repair. Hence it consumes ~100 g/day of glucose in a 70 kg individual. Glucose enters the brain by insulin-insensitive facilitated diffusion across the blood-brain barrier, and enters brain cells mainly via a range of insulin-insensitive glucose transporters. Within the cell, glucose is phosphorylated by hexokinase, an enzyme of such high affinity towards glucose that the rate of glucose phosphorylation approximates the enzyme’s maximum reaction rate. Blood-brain glucose transfer obeys Michaelis-Menten kinetics, such that the glucose extraction fraction rises in hypoglycaemia and falls during hyperglycaemia. Insulin also crosses the blood brain barrier and binds to receptors on neurons and glial cells. There is controversy as to whether insulin resistance is present in the CNS, but emerging data suggests that insulin insensitivity may play an important role in the pathogenesis of obesity, type 2 diabetes, and Alzheimer’s disease. GLP-1 may also modulate cerebral glucose metabolism with neuroprotective effects in the presence of hyperglycaemia.

Cerebral glucose metabolism

Figure 1: [Click to enlarge] The Michaelis-Menten Meter is a graphical rendition of the Michaelis-Menten equation applied to transport across the blood-brain barrier in both directions, the difference between the fluxes being equal to the rate of glucose phosphorylation. In the three panels, the abscissa is the apparent permeability-surface area product or clearance of glucose. The ordinate is the flux of glucose in either direction. The ratio between the flux and the clearance is the concentration of glucose in the circulation and brain tissue, respectively, as indicated on the quarter-circle to which the arrows point. The black horizontal lines indicate the fluxes of glucose in the three conditions shown in the panels. The net glucose transfer, equal to the glucose consumption, is 0.25 mol/g/min in all three states exemplified in the panels. In hypoglycemia, the plasma glucose is 2.7 mM and the brain glucose 0.55 mM. In normoglycemia, the plasma glucose is 5 mM and the brain glucose 1.7 mM. In hyperglycemia, the plasma glucose is 12 mM and the brain glucose 4.1 mM. Note that the difference between plasma and brain glucose increases with increasing plasma glucose, as the glucose consumption remains constant.
Figure 1: [Click to enlarge] The Michaelis-Menten Meter is a graphical rendition of the Michaelis-Menten equation applied to transport across the blood-brain barrier in both directions, the difference between the fluxes being equal to the rate of glucose phosphorylation. In the three panels, the abscissa is the apparent permeability-surface area product or clearance of glucose. The ordinate is the flux of glucose in either direction. The ratio between the flux and the clearance is the concentration of glucose in the circulation and brain tissue, respectively, as indicated on the quarter-circle to which the arrows point. The black horizontal lines indicate the fluxes of glucose in the three conditions shown in the panels. The net glucose transfer, equal to the glucose consumption, is 0.25 mol/g/min in all three states exemplified in the panels. In hypoglycemia, the plasma glucose is 2.7 mM and the brain glucose 0.55 mM. In normoglycemia, the plasma glucose is 5 mM and the brain glucose 1.7 mM. In hyperglycemia, the plasma glucose is 12 mM and the brain glucose 4.1 mM. Note that the difference between plasma and brain glucose increases with increasing plasma glucose, as the glucose consumption remains constant.
Maps of the changes of blood flow, oxygen use, and glucose consumption in the brain demonstrate complex patterns of coupling among changes of neuronal activity and regional circulation and metabolism [1][2]. The increase of oxidative metabolism during activation is small, but the increases of glucose utilization and blood flow vary as much as 50% above the baseline [3]. Glucose enters the brain tissue from plasma by transport across the two membranes of the endothelium of the blood-brain barrier (BBB) by facilitated diffusion mediated by glucose transporters. At normoglycemia, the glucose consumption establishes a glucose concentration of approximately one third of the plasma glucose concentration in brain cells and extracellular space (figure 1).

Different brain regions have somewhat different energy requirements, dependent on the fraction of gray matter and the average neuronal activity. In the cells of the brain tissue, glucose is phosphorylated by hexokinase to glucose-6-phosphate that is metabolized further, mainly in the glycolytic pathway, where it is converted to pyruvate. Glucose-6-phosphate is also substrate for the pentose phosphate shunt and the generation of glycogen. Pyruvate is metabolized either in the Krebs cycle after transport into the mitochondria, or converted to lactate by means of lactate dehydrogenase. A major fraction of the pyruvate transported into brain mitochondria is devoted to the oxidative phosphorylation of ADP to ATP, but the exact fraction is not known with certainty in vivo. The affinity of hexokinase to glucose is so high that the enzyme is saturated at normal intracellular glucose concentration and therefore the rate of glucose phosphorylation is close to the maximal velocity of the hexokinase reaction [4].

In a number of studies, the rate of blood flow to the brain has been found to be close to proportional to the glucose phosphorylation rate, but the mechanism is uncertain [5]. The brain’s energy metabolism almost exclusively depends on the constant supply of glucose, but the supply of glucose for normal brain function is not very sensitive to blood flow fluctuations. As metabolically highly active cells (ATP use in cortex: 0.5 mol/s/m3 [6]), neurons need the energy for maintenance of ion gradients in support of the depolarization established by synaptic transmission, as well as for axonal and dendritic transport and structural renovation of brain tissue [7].

Cerebral glucose transporters

Most human cells import glucose by members of the GLUT (SLC2A) family of membrane transport proteins (see review [8]). Eight GLUT proteins are identified in the brain, including transporters for substrates other than glucose, such as fructose and myoinositol. Of these, GLUT1 is insulin-insensitive and abundant in the BBB and in astrocytes, regulated mainly by steady-state levels of plasma glucose and possibly glucagon-like peptide-1. GLUT2 appears to serve glucose sensors in the brain. The insulin-insensitive GLUT3 ensures efficient glucose uptake by neurons in both dendrites and axons. The translocatable GLUT4 is present in neurons of several brain areas, notably regions associated with control of the motor system, and the locations match those of insulin receptors. GLUT5 and GLUT7 are present at low levels in the brain and have specificity for fructose. GLUT6 is expressed in the brain but has low affinity to glucose. Studies of mice suggest roles of GLUT8 in hippocampal neuronal proliferation. GLUT13 is a myoinositol transporter expressed primarily in the brain and is the only GLUT protein that appears to function as a proton-coupled symporter.

Hypo- and hyperglycemia

Stable concentrations of glucose in brain tissue are important to the regulation of glucose concentration in brain. Severe hypoglycemia limits the net glucose flux across the two membranes of the blood-brain barrier and may reduce brain glucose to negligible levels (figure 1). Moderate hypoglycemia on the other hand is not limiting for brain glucose metabolism in non-diabetic subjects [9]. Hyperglycemia raises the brain glucose concentration (figure 1) and may worsen the outcome of stroke. Recent evidence reveals that the increased glucose content markedly affects cognition and memory [10], tentatively due to conversion of excess glucose to sorbitol and fructose. The overflow affects several intracellular cascades, including those associated with critically advanced glycation end products and reactive oxygen species associated with Alzheimer’s disease.

The equation of Michaelis and Menten (1913) [11] describes the simple relationship between glucose transported across the BBB and the glucose concentrations in plasma and brain tissue [12]. The relation in turn is consistent with an inverse relation between the glucose extraction and the glucose concentration, such that extraction declines in hyperglycemia and rises in hypoglycemia. It remains uncertain how insulin-independent glucose transport across the BBB is regulated by factors other than the concentration of glucose and the maximum capacity of the GLUT1 transporters. By extension, the Michaelis-Menten equation also describes the relationship between the rate of cerebral glucose metabolism and the BBB transport.

In vitro studies suggest that fluctuating glucose levels have a greater adverse effect on neuronal cell energy regulation than sustained levels of high or low glucose [13], implying the possible need for stabilizing drugs, although a current debate on the metabolic significance of glycemic variation in determining long term outcome in diabetes is inconclusive. Glycemic variability nonetheless could determine micro- and macrovascular effects in T2D [14].

Insulin and the brain

Type 2 diabetes (T2D) is characterized by peripheral insulin resistance, but it is debated whether the brain also is a target of insulin resistance. Insulin crosses the blood-brain barrier via a saturable transport system [15] and binds to insulin receptors on neurons and glial cells. Some studies relate insulin to brain glucose metabolism, but other reports conclude that the effect of insulin is already maximal at fasting concentrations in healthy subjects. At postprandial and physiological levels, insulin stimulates brain glucose metabolism in patients with impaired glucose tolerance [16]. Interestingly, the cerebral glucose metabolism decreases with plasma insulin concentrations below the physiological fasting levels [17][18], implying that the insulin effect is saturated at fasting concentrations in healthy subjects. In contrast, low plasma insulin concentrations appear not to lower brain glucose metabolism in patients with impaired glucose tolerance [18].

In addition to metabolic measures of the cerebral insulin sensitivity, this parameter is assessed by the insulin-stimulated change in theta and beta encephalographic activity assessed by magnetoencephalography (MEG). The authors report that high insulin sensitivity of the human brain facilitates loss of body weight and body fat during lifestyle intervention [19]. Other studies confirm that the brain is an insulin-sensitive organ that may play an important role in the regulation of energy balance and glucose homeostasis, in association with other nutrition and adiposity signals. Diet seems to play a role in inducing a state of central insulin resistance, and obesity may further reduce the neuronal sensitivity to insulin which leads to a hyperinsulinemic state, followed by hyperglycemia, and thus generates a cycle that could progress to T2D, in combination with beta-cell dysfunction [20]. Insulin has a catabolic effect and appears to influence memory functions by modulating neurotransmitter release and synaptic plasticity [21].

Glucagon-like peptide-1 and the brain

Glucagon-like peptide-1 (GLP-1) is an insulinotropic incretin hormone with extrapancreatic effects. Analogues are used to treat T2D and studies reveal significant effects in regions of brain tissue that regulate appetite and satiety. GLP-1 interacts with the autonomic nervous system, and emerging preclinical findings indicate a potential neuroprotective role of the peptide, e.g., in models of stroke and in neurodegenerative disorders. GLP-1 is a molecule of interest to the understanding of brain energy metabolism, as Michaelis-Menten kinetics reveals glucose-dependent impact of GLP-1 on blood-brain glucose transfer and metabolism [22]. Indeed, the effects of GLP-1 receptor activation depend on the glucose concentration and relative affinities of the kinetic steps both in vitro and in vivo. In the brain, GLP-1 appears to affect both transport of glucose across the BBB and the metabolism of glucose, in addition to the effect on the plasma glucose concentration, with the action of GLP-1 on glucose homeostasis in the brain mimicking that known for the pancreas: At pharmacologically elevated levels, GLP-1 has no deleterious effect on brain glucose transport in hypoglycemia and does not exacerbate the effect of hypoglycaemia [23]. During hyperglycemia, one study suggests that GLP-1 elicits the combined effects of lowered intracerebral glucose content and increased net clearance [24]. Hence, GLP-1 may attenuate the fluctuation of brain glucose levels in response to changing plasma glucose, which is likely to be an important neuroprotective effect in hyperglycemia.

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