Brain Glucose Transport Research Articles

Síndrome de deficiencia del transportador de glucosa tipo 1 (SDGLUT-1) tratado con dieta cetogénica: Caso clínico

The glucose transporter type 1 deficiency syndrome (GLUT-1 SD) (OMIM 606777) is an inborn error of metabolism of brain glucose transport. The characteristic clinical manifestations are seizures, hypotonia, developmental delay, microcephaly and hypoglycorrhachia. We report a girl with normal weight and height at birth. At 6 weeks of age she started with convulsions reaching up to 20 myoclonic seizures a day. She was treated with valproate, phenobarbital and carbamazepine without response. Blood analysis including aminoacids and acylcarnitines were all normal. The brain MRI showed frontal atrophy with an increased subarachnoidal space and Electroencephalography was abnormal. Blood glucose was 84 mg/dl and spinal fluid glucose 26 mg/dl with a ratio of 0.31 (Normal Ratio >0.65+/-00.1). These results suggested the diagnosis of GLUT-1 SD, and was confirmed with erythrocyte glucose uptake of 44% (Normal range 80-100%). A molecular study found the mutation 969del, C971T in exon 6 of the gene Glut-1. Treatment with a ketogenic diet was started immediately and after 7 days with this diet seizures ceased. Anticonvulsants were progressively suspended. At present, the patient is 6 years old, she continues on a ketogenic diet and supplements with L-carnitine, lipoic acid, vitamins and minerals. Growth and development are normal with an intelligence quotient of 103. It is concluded that it is necessary to include GLUT-1 SD in the differential diagnosis of children with early seizures that are non responsive to pharmacological treatment.

Effects of Peroxisome Proliferator-Activated Receptor Gamma Agonists on Brain Glucose and Glutamate Transporters after Stress in Rats

Repeated stress causes an energy-compromised status in the brain, with a decrease in glucose utilization by the brain cells, which might account for excitotoxicity processes seen in this condition. In fact, brain glucose metabolism mechanisms are impaired in some neurodegenerative disorders, including stress-related neuropsychopathologies. More recently, it has been demonstrated that some synthetic peroxisome proliferator-activated receptor gamma (PPARgamma) agonists increase glucose utilization in rat cortical slices and astrocytes, as well as inhibit brain oxidative damage after repeated stress, which add support for considering these drugs as potential neuroprotective agents. To assess if stress causes glucose utilization impairment in the brain and to study the mechanisms by which this effect is achieved, young-adult male Wistar rats (control and immobilized for 6 h during 7 or 14 consecutive days, S7, S14) were i.p. injected with the natural ligand 15-deoxy-Delta-12,14-prostaglandin J2 (PGJ2, 120 microg/kg) or the high-affinity ligand rosiglitazone (RG, 3 mg/kg) at the onset of stress. Repeated immobilization during 1 or 2 weeks produces a decrease in brain cortical synaptosomal glucose uptake, and this effect was prevented by treatment with both natural and synthetic PPARgamma ligands by restoring protein expression of the neuronal glucose transporter, GLUT-3 in membrane fractions. On the other hand, treatment with PPARgamma ligands prevents stress-induced ATP loss in rat brain. Finally, repeated immobilization stress also produces a decrease in brain cortical synaptosomal glutamate uptake, and this effect was prevented by treatment with PPARgamma ligands by restoring synaptosomal protein expression of the glial glutamate transporter, EAAT2. In summary, our results demonstrate that 15d-PGJ2 and the thiazolidinedione rosiglitazone increase neuronal glucose metabolism, restore brain ATP levels and prevent the impairment in glutamate uptake mechanisms induced by exposure to stress, suggesting that this class of drugs may be therapeutically useful in conditions in which brain glucose levels or availability are limited after exposure to stress.

The Blood–Brain Barrier and Epilepsy

During the past several years, there has been increasing interest in the role of the blood-brain barrier (BBB) in epilepsy. Advances in neuroradiology have enhanced our ability to image and study the human cerebrovasculature, and further developments in the research of metabolic deficiencies linked to seizure disorders (e.g., GLUT1 deficiency), neuroinflammation, and multiple drug resistance to antiepileptic drugs (AEDs) have amplified the significance of the BBB's relationship to epilepsy. Prior to 1986, BBB research in epilepsy focused on three main areas: ultrastructural studies, brain glucose availability and transport, and clinical uses of AEDs. However, contrast-based imaging techniques and medical procedures such as BBB disruption provided a framework that demonstrated that the BBB could be reversibly disrupted by pathologic or iatrogenic manipulations, with important implications in terms of CNS drug delivery to "multiple drug resistant" brain. This concept of BBB breakdown for therapeutic purposes has also unveiled a previously unrecognized role for BBB failure as a possible etiologic mechanism in epileptogenesis. Finally, a growing body of evidence has shown that inflammatory mechanisms may participate in the pathological changes observed in epileptic brain, with increasing awareness that blood-borne cells or signals may participate in epileptogenesis by virtue of a leaky BBB. In this article we will review the relationships between BBB function and epilepsy. In particular, we will illustrate consensus and divergence between clinical reality and animal studies.

Differential changes in brain glucose metabolism during hypoglycaemia accompany loss of hypoglycaemia awareness in men with type 1 diabetes mellitus. An [11C]-3-O-methyl-d-glucose PET study

Hypoglycaemia unawareness in type 1 diabetes increases the risk of severe hypoglycaemia and impairs quality of life for people with diabetes. To explore the central mechanisms of hypoglycaemia awareness, we used [11C]-3-O-methyl-D-glucose (CMG) positron emission tomography (PET) to measure changes in global and regional brain glucose metabolism between euglycaemia and hypoglycaemia in aware and unaware diabetic subjects. Twelve men with type 1 diabetes, of whom six were characterised as aware and six as unaware of hypoglycaemia, underwent two CMG-PET brain scans while plasma glucose was controlled by insulin and glucose infusion either at euglycaemia (5 mmol/l) or at hypoglycaemia (2.6 mmol/l) in random order. With hypoglycaemia, symptoms and sweating occurred only in the aware group. Brain glucose content fell in both groups (p=0.0002; aware, 1.18+/-0.45 to 0.02+/-0.2 mmol/l; unaware, 1.07+/-0.46 to 0.19+/-0.23 mmol/l), with a relative increase in tracer uptake in prefrontal cortical regions, including the anterior cingulate. No detectable differences were found between groups in global brain glucose transport parameters (K1, k2). The cerebral metabolic rate for glucose (CMRglc) showed a relative rise in the aware subjects (11.839+/-2.432 to 13.958+/-2.372) and a fall in the unaware subjects (from 12.457+/-1.938 to 10.16+/-0.801 micromol 100 g(-1) min(-1), p=0.043). Hypoglycaemia is associated with reduced brain glucose content in aware and unaware subjects, with a relative preservation of metabolism in areas associated with sympathetic activation. The relative rise in global glucose metabolic rate seen in aware subjects during hypoglycaemia contrasted with the relative fall in the unaware subjects and suggests that cortical neuronal activation is a necessary correlate of the state of hypoglycaemia awareness.

(n-3) Polyunsaturated Fatty Acid Deficiency Reduces the Expression of Both Isoforms of the Brain Glucose Transporter GLUT1 in Rats

The altered neuron activity of rats deficient in (n-3) PUFAs may be due in part to a decrease in brain glucose utilization and glucose transport. We measured the glucose transporter protein GLUT1 isoforms at the blood-brain barrier (55-kDa) and in astrocytes (45-kDa) by Western immunoblotting and their mRNA by real time RT-PCR analysis in the cerebral cortex of adult male rats fed diets lacking (n-3) fatty acids (1st generation). The neuron glucose transporter GLUT3 was also assayed. The fatty acids in the phosphatidylcholine (PC), ethanolamine phosphoglycerolipid (EPG), and phosphatidylserine (PS) fractions of isolated microvessels and homogenates of the cerebral cortex were determined. The levels of (n-6) PUFAs [mainly arachidonic acid, 20:4(n-6)] in the phospholipid fractions of microvessels were higher and the levels of (n-3) PUFAs [mainly docosahexaenoic acid, 22:6(n-3)] were lower than in cerebral cortex homogenates. The microvessels and cortex of rats fed the (n-3) PUFA-deficient diet had 50% of the control 22:6(n-3) contents; 22:6(n-3) was replaced by 22:5(n-6). The 55-kDa GLUT1 immunoreactivity in (n-3) PUFA-deficient microvessels was decreased (down 25%, P < 0.01), as was the 45 kDa-GLUT1 in the homogenate (down 30%, P < 0.01). But the amount of immunoreactivity of GLUT3 did not change. The amount of GLUT1 mRNA was not affected by the (n-3) PUFA-deficient diet. These results suggest that the decreased glucose utilization in the cerebral cortex of (n-3) PUFA-deficient rats is due to reduced amounts of the 2 isoforms of GLUT1, indicating post-transcriptional regulation of GLUT1 synthesis.

Brain glucose concentrations in poorly controlled diabetes mellitus as measured by high-field magnetic resonance spectroscopy

Hyperglycemia and diabetes alter the function and metabolism of many tissues. The effect on the brain remains poorly defined, but some animal data suggest that chronic hyperglycemia reduces rates of brain glucose transport and/or metabolism. To address this question in human beings, we measured glucose in the occipital cortex of patients with poorly controlled diabetes and healthy volunteers at the same levels of plasma glucose using proton magnetic resonance spectroscopy. Fourteen patients with poorly controlled diabetes (hemoglobin A 1c = 9.8% ± 1.7%, mean ± SD) and 14 healthy volunteers similar with respect to age, sex, and body mass index were studied at a plasma glucose of 300 mg/dL. Brain glucose concentrations of patients with poorly controlled diabetes were lower but not statistically different from those of control subjects (4.7 ± 0.9 vs 5.3 ± 1.1 μmol/g wet wt; P = .1). Our sample size gave 80% power to detect a difference as small as 1.1 μmol/g wet wt. We conclude that chronic hyperglycemia in diabetes does not alter brain glucose concentrations in human subjects.

Estrogen and Cognition, with a Focus on Alzheimer's Disease

Cognitive aging is associated with decreases in memory, attention, and visual/motor performance and skills. Dementia consists of loss of memory and other cognitive abilities, associated with social or occupational impairment. Potential neuroprotective effects of estrogen include lowering beta-amyloid, enhancing cholinergic function, promoting synaptic plasticity and nerve process growth, reducing oxidative stress, and enhancing brain glucose transport. Observational and longitudinal studies suggest that hormone therapy may attenuate age-associated cognitive impairment or decrease Alzheimer's disease but this has not been confirmed by randomized clinical trials. A critical window of time may exist around the menopause when hormone therapy may delay or decrease cognitive changes; however, hormone therapy initiated in the late postmenopause does not improve global cognition and may increase dementia risk.

Brain glucose concentrations in healthy humans subjected to recurrent hypoglycemia

Mechanisms responsible for hypoglycemia unawareness remain unknown. Previously, we found that patients with type 1 diabetes and hypoglycemia unawareness had increased brain glucose concentrations as measured by (1)H-magnetic resonance spectroscopy (MRS) compared with controls measured under the same metabolic condition, suggesting that an alteration in brain glucose transport and/or metabolism may play a role in the pathogenesis of hypoglycemia unawareness. To determine whether the brain glucose concentration is altered in normal subjects subjected to recurrent hypoglycemia, we compared the brain glucose concentrations measured in healthy subjects after three episodes of hypoglycemia to blunt the counterregulatory response over 24 hr and compared this value with that measured at a time remote from the antecedent hypoglycemia protocol. Sixteen subjects (9 M/7 F, age 36 +/- 10 years, mean +/- SD) underwent three hypoglycemic clamps for 30 min at 8 AM (0 hr), 5 PM (9 hr), and 7 AM (24 hr). After the third hypoglycemic clamp, subjects underwent a hyperglycemic clamp during which brain glucose concentration was measured by MRS at 4 T. Brain glucose concentration after repeated hypoglycemia was not different from the brain glucose concentration measured in the same subjects during a control study (5.1 +/- 0.8 vs. 4.5 +/- 0.5 mumol/g wet weight, respectively, P = 0.05). These observations suggest that brain glucose transport or metabolism is not altered following short episodes of recurrent hypoglycemia in healthy human volunteers.

Brain glucose concentrations in patients with type 1 diabetes and hypoglycemia unawareness

Although it is well established that recurrent hypoglycemia leads to hypoglycemia unawareness, the mechanisms responsible for this are unknown. One hypothesis is that recurrent hypoglycemia alters brain glucose transport or metabolism. We measured steady-state brain glucose concentrations during a glucose clamp to determine whether subjects with type 1 diabetes and hypoglycemia unawareness may have altered cerebral glucose transport or metabolism after exposure to recurrent hypoglycemia. We compared 14 subjects with diabetes and hypoglycemia unawareness to 27 healthy control subjects. Brain glucose concentrations were measured under similar metabolic conditions using in vivo (1)H nuclear magnetic resonance (NMR) spectroscopy at 4 Tesla during a hyperglycemic clamp (plasma glucose = 16.7 mmol/l) with somatostatin and insulin. Subjects with type 1 diabetes and hypoglycemia unawareness had significantly higher brain glucose concentrations compared to that in controls under the same conditions (5.5 +/- 0.3 vs. 4.7 +/- 0.1 micromol/g wet weight, P = 0.016). These data suggest that changes in brain glucose transport or metabolism may occur as a result of recurrent hypoglycemia.

Glucose transporter expression in the central nervous system: relationship to synaptic function

The family of facilitative glucose transporter (GLUT) proteins is responsible for the entry of glucose into cells throughout the periphery and the brain. The expression, regulation and activity of GLUTs play an essential role in neuronal homeostasis, since glucose represents the primary energy source for the brain. Brain GLUTs exhibit both cell type and region specific localizations suggesting that the transport of glucose across the blood–brain barrier is tightly regulated and compartmentalized. As seen in the periphery, insulin-sensitive GLUTs are expressed in the brain and therefore may participate in the central actions of insulin. The aim of this review will be to discuss the localization of GLUTs expressed in the central nervous system (CNS), with a special emphasis upon the recently identified GLUT isoforms. In addition, we will discuss the regulation, activity and insulin-stimulated trafficking of GLUTs in the CNS, especially in relation to the centrally mediated actions of insulin and glucose.

For want of a nail. ramifications of a single gene deletion, dystrophin, in the brain of the mouse.

Lack of expression of a single gene, dystrophin, causes the severe, progressive muscle wasting and mental deficits characteristic of Duchenne muscular dystrophy. In this work, we investigated the impact of dystrophin deletion on expression of other genes in the brain cortex, hippocampus and cerebellum using the murine homologue, the mdx mouse, and RT-PCR. Expression of the brain glucose transporters GLUT1 and GLUT2 was found to be decreased, as were some subunits of the GABAA and nicotinic acetylcholine receptors. Genes involved in bioenergetic homeostasis, such as the mitochondrial creatine kinase and the gamma subunit of ATP synthase were also found to be abnormally expressed, while expression of the structural proteins beta-dystrobrevin and rapsyn was also significantly affected. We relate these findings to known functional deficits and discuss the possible mechanisms behind the altered gene expression.

Postnatal hypoxic-ischemic brain injury alters mechanisms mediating neuronal glucose transport

We examined the effect of hypoxic ischemia and hypoxia vs. normoxia on postnatal murine brain substrate transporter concentrations and function. We detected a transient increase in the neuronal brain glucose transporter isoform (GLUT-3) in response to hypoxic ischemia after 4 h of reoxygenation. This increase was associated with no change in GLUT-1 (blood-brain barrier/glial isoform), monocarboxylate transporter isoforms 1 and 2, synapsin I (neuronal marker), or Bax (proapoptotic protein) but with a modest increase in Bcl-2 (antiapoptotic mitochondrial protein) protein concentrations. At 24 h of reoxygenation, the increase in GLUT-3 disappeared but was associated with a decline in Bcl-2 protein concentrations and the Bcl2:Bax ratio, an increase in caspase-3 enzyme activity (apoptotic effector enzyme), and extensive DNA fragmentation, which persisted later in time (48 h) only in the hippocampus. Hypoxia alone in the absence of ischemia was associated with a transient but modest increase in GLUT-3 and synapsin I protein concentrations, which did not cause significant apoptosis and/or necrosis. Assessment of glucose transporter function by 2-deoxyglucose (2-DG) uptake using two distinct techniques, namely positron emission tomography (PET) and the modified Sokoloff method, revealed a discrepancy due to glucose uptake by extracranial Harderian glands that masked the accurate detection of intracranial brain glucose uptake by PET scanning. The modified Sokoloff method assessing 2-DG uptake revealed that the transient increase in GLUT-3 was critical in protecting against a decline in brain glucose uptake. We conclude that hypoxic-ischemic brain injury is associated with transient compensatory changes targeted at protecting glucose delivery to fuel cellular energy metabolism, which then may delay the processes of apoptosis and cell necrosis.

A ketogenic diet increases brain insulin-like growth factor receptor and glucose transporter gene expression.

A ketogenic diet suppresses seizure activity in children and in juvenile rats. To investigate whether alteration in brain IGF activity could be involved in the beneficial effects of the ketogenic diet, we examined the effects of this diet on IGF system gene expression in the rat brain. Juvenile rats were fed one of three different diets for 7 d: ad libitum standard rat chow (AL-Std), calorie-restricted standard chow (CR-Std), or a calorie-restricted ketogenic diet (CR-Ket). The calorie-restricted diets contained 90% of the rats' calculated energy requirements. The AL-Std diet group increased in weight, whereas the two CR groups merely maintained their weight during the 7-d diet. Glucose levels were significantly reduced in both CR groups compared with the AL-Std group, but only the CR-Ket group developed ketonemia. IGF1 mRNA levels were reduced by 30-50% in most brain regions in both CR groups. IGF1 receptor (IGF1R) mRNA levels were decreased in the CR-Std group but were increased in the CR-Ket diet group. Brain IGF binding protein (IGFBP)-2 and -5 mRNA levels were not altered by diet, but IGFBP-3 mRNA levels were markedly increased by the ketogenic diet while not altered by calorie restriction alone. Brain glucose transporter expression was also investigated in this study. Glucose transporter (GLUT) 4 mRNA levels were quite low and not appreciably altered by the different diets. Parenchymal GLUT1 mRNA levels were increased by the CR-Ket diet, but endothelial GLUT1 mRNA levels were not affected. Neuronal GLUT3 expression was decreased with the CR-Std diet and increased with the CR-Ket diet, in parallel with the IGF1R pattern. These observations reveal divergent effects of dietary caloric content and macronutrient composition on brain IGF system and GLUT expression. In addition, the data may be consistent with a role for enhanced IGF1R and GLUT expression in ketogenic diet-induced seizure suppression.

Effect of deep pentobarbital anesthesia on neurotransmitter metabolism in vivo: on the correlation of total glucose consumption with glutamatergic action.

The effect of deep barbiturate anesthesia on brain glucose transport, TCA cycle flux, and aspartate, glutamate, and glutamine metabolism was assessed in the rat brain using 13C nuclear magnetic resonance spectroscopy at 9.4 T in conjunction with [1-13C] glucose infusions. Brain glucose concentrations were elevated, consistent with a twofold reduced cerebral metabolic rate for glucose (CMRglc) compared with light alpha-chloralose anesthesia. Using a mathematical model of neurotransmitter metabolism, several metabolic reaction rates were extracted from the rate of label incorporation. Total oxidative glucose metabolism, CMRglc(ox), was 0.33 +/- 0.03 micromol x g(-1) x min(-1). The neuronal TCA cycle rate was similar to that in the glia, 0.35 +/- 0.03 micromol x g(-1) x min(-1) and 0.26 +/- 0.06 micromol x g(-1) x min(-1), respectively, suggesting that neuronal energy metabolism was mainly affected. The rate of pyruvate carboxylation was 0.03 +/- 0.01 micromol x g(-1) x min(-1). The exchange rate between cytosolic glutamate and mitochondrial 2-oxoglutarate, Vx, was equal to the rate of neuronal pyruvate dehydrogenase flux. This indicates that Vx is coupled to CMRglc(ox), implying that the malate-aspartate shuttle is the major mechanism that facilitates label exchange across the inner mitochondrial membrane. The apparent rate of glutamatergic neurotransmission, V(NT), was 0.04 +/- 0.01 micromol x g x min, consistent with strong reductions in electrical activity. However, the rates of cerebral oxidative glucose metabolism and glutamatergic neurotransmission, CMRglc(ox)/V(NT), did not correlate with a 1:1 stoichiometry.

Immunohistochemical localization and quantification of glucose transporters in the mouse brain

A family of seven facilitative glucose transporters (Glut1–5, 7 and 8) mediates the cellular uptake of glucose. In the brain, Glut2, Glut5 and Glut8 are found at relatively low levels whereas Glut1, Glut3 and Glut4 were reported in abundance in several brain regions. Using immunofluorescence, this study investigated, compared and quantified the localization of the brain major glucose transporters, Glut1, Glut3 and Glut4, in the different cerebral areas of CD1 mice. Most of the staining of Glut1, Glut3 and Glut4 in the mouse brain coincides with observations made in rats. The results confirm the cortical neuropil distribution of Glut3, the prominence of this transporter in the mossy fiber field of the hippocampus and the Glut3 and Glut4 immunostaining of the hippocampal pyramidal cell layer. The present study also reports novel localizations of the transporters such as the presence of Glut3 in neuronal perikarya, Glut4-labeled neurons in the CA3 of the hippocampus and the subiculum. In the cerebellum, Glut3 shows subcellular localization to the base of the Purkinje cell bodies near the axon hillock. Furthermore, an important population of Golgi cells was found to be strongly immunostained for Glut4 in the granular cell layer of the cerebellum. The quantification results suggest that the relative abundance of Glut1 in the frontal and motor cortices coincides well with the high-energy demands of these brain regions. However, the Glut4-selective abundance in cerebral motor areas supports its suggested role in providing the energy needed for the control of the motor activity. The reported neuropil distribution of Glut3 seems to uphold its suggested role in synaptic energy provision and neurotransmitter synthesis. We conclude that the cellular and regional distributions of the glucose transporters in the rodent brain seem to be relevant to their corresponding functions.

Expression, regulation, and functional role of glucose transporters (GLUTs) in brain

Publisher Summary Glucose is the primary source of energy for the mammalian brain. As in most other tissues, glucose transport in the central nervous system (CNS) is mediated by facilitative glucose transporter proteins, glucose transporters (GLUTs). However, to date a thorough understanding of the mechanisms regulating glucose transport in the brain lags behind what is known in the “periphery.” The objective of this chapter is to expand the working knowledge of brain glucose uptake and utilization in the context of recent advances in the transport field. As a starting point, current molecular models of the GLUT protein structure are presented and compared with the known structures of other related transporters. The various structures may provide insights into the mechanisms by which glucose is transported across cell membranes. Data regarding the different GLUT isoforms found in brain and their regional distribution are summarized. There has been a virtual explosion within the past two years resulting in a doubling of the members of the family of facilitative glucose transporters. This chapter classifies the new members of this family as mammalian glucose transporters and shows their specific neural locations and functions in the CNS.

In vivo measurements of brain glucose transport using the reversible Michaelis-Menten model and simultaneous measurements of cerebral blood flow changes during hypoglycemia.

Glucose is the major substrate that sustains normal brain function. When the brain glucose concentration approaches zero, glucose transport across the blood-brain barrier becomes rate limiting for metabolism during, for example, increased metabolic activity and hypoglycemia. Steady-state brain glucose concentrations in alpha-chloralose anesthetized rats were measured noninvasively as a function of plasma glucose. The relation between brain and plasma glucose was linear at 4.5 to 30 mmol/L plasma glucose, which is consistent with the reversible Michaelis-Menten model. When the model was fitted to the brain glucose measurements, the apparent Michaelis-Menten constant, Kt, was 3.3 +/- 1.0 mmol/L, and the ratio of the maximal transport rate relative to CMRglc, Tmax/CMRglc, was 2.7 +/- 0.1. This Kt is comparable to the authors' previous human data, suggesting that glucose transport kinetics in humans and rats are similar. Cerebral blood flow (CBF) was simultaneously assessed and constant above 2 mmol/L plasma glucose at 73 +/- 6 mL 100 g(-1) min(-1). Extrapolation of the reversible Michaelis-Menten model to hypoglycemia correctly predicted the plasma glucose concentration (2.1 +/- 0.6 mmol/L) at which brain glucose concentrations approached zero. At this point, CBF increased sharply by 57% +/- 22%, suggesting that brain glucose concentration is the signal that triggers defense mechanisms aimed at improving glucose delivery to the brain during hypoglycemia.

The effect of maternal malnutrition during pregnancy in the rat on the offspring’s weight, glucose uptake, glucose transporter protein levels and behaviors

Intrauterine growth retardation (IUGR) is associated with multiple molecular and physiological changes in the offspring. In the current study, offspring of dams acutely fasted on days 17–19 were compared to the offspring of non-food deprived dams with respect to postnatal growth, glucose uptake, brain glucose transporter Glut 1 protein levels and age-specific behaviors. Further, in a chronic study, control mothers were given ad lib. access to a nutritionally balanced liquid diet from day 0 until day 18 or day 20 of pregnancy. These offspring were compared to the offspring of mothers who consumed 90% of the ad lib mothers’ calories. Overall, the malnourished offspring had: 1) IUGR, 2) small changes in brain glucose uptake and in Glut 1 transport protein content and, 3) minor alterations in their behavior. In both models, pups whose dams were malnourished weighed less than control offspring at birth and the growth retardation was sustained through six months of age. In the acute model, behavioral comparisons revealed that rats from acutely malnourished litters were impaired only on incline descent, requiring more time to descend than did the non-malnourished control pups. Brain glucose uptake showed only modest differences. Western blotting of glucose transporter proteins indicated that there was little correlation between brain glucose uptake and Glut 1 protein levels in pups from either malnourished or control litters. At 60 days, malnourished offspring were glucose intolerant relative to offspring from control litters.

Brain glucose transporters: relationship to local energy demand.

Glucose, the major fuel in the brain, is transported across the cell membranes by facilitated diffusion mediated by glucose transporter proteins. Essentially two types of glucose transporters are localized in the membranes of brain endothelial cells, astrocytes, and neurons. Their densities are well adjusted to changes in local energy demand.

Studies of metabolic compartmentation and glucose transport using in vivo MRS.

Organs consist of several types of cells with specialized functions. This cellular localization of function is often referred to as compartmentation. Due to the intrinsic low sensitivity of MR methods it is generally not possible in vivo to obtain images or spectra of single cells. Instead the MRS signal is the sum of the signal from millions of cells and multiple cell types. A major challenge in using MRS to study biological processes such as metabolism and transport is to devise measurements that provide cell-specific information from this mix. Fortunately nature has helped the MR scientist by in several cases nearly completely localizing metabolic pathways and their associated metabolites in specific cell types. The chemical specificity of MRS allows the concentrations and synthesis rates of these metabolites to be measured, providing information about the compartmentation of metabolism and function. In this review examples are presented from MRS studies of metabolic trafficking between neurons and astrocytes in the brain, brain glucose transport, and the role of muscle glucose transport in insulin resistance and diabetes. The concepts and approaches used in these studies are generally applicable for studying cellular metabolic compartmentation in a wide range of systems.