Brain Glucose Concentrations Research Articles

Does hyperphenylalaninemia induce brain glucose hypometabolism? Cerebral spinal fluid findings in treated adult phenylketonuric patients

Despite numerous studies in human patients and animal models for phenylketonuria (PKU; OMIM#261600), the pathophysiology of PKU and the underlying causes of brain dysfunction and cognitive problems in PKU patients are not well understood. In this study, lumbar cerebral spinal fluid (CSF) was obtained immediately after blood sampling from early-treated adult PKU patients who had fasted overnight. Metabolite and amino acid concentrations in the CSF of PKU patients were compared with those of non-PKU controls. The CSF concentrations and CSF/plasma ratios for glucose and lactate were found to be below normal, similar to what has been reported for glucose transporter1 (GLUT1) deficiency patients who exhibit many of the same clinical symptoms as untreated PKU patients. CSF glucose and lactate levels were negatively correlated with CSF phenylalanine (Phe), while CSF glutamine and glutamate levels were positively correlated with CSF Phe levels. Plasma glucose levels were negatively correlated with plasma Phe concentrations in PKU subjects, which partly explains the reduced CSF glucose concentrations. Although brain glucose concentrations are unlikely to be low enough to impair brain glucose utilization, it is possible that the metabolism of Phe in the brain to produce phenyllactate, which can be transported across the blood-brain barrier to the blood, may consume glucose and/or lactate to generate the carbon backbone for glutamate. This glutamate is then converted to glutamine and carries the Phe-derived ammonia from the brain to the blood. While this mechanism remains to be tested, it may explain the correlations of CSF glutamine, glucose, and lactate concentrations with CSF Phe.

Intranasal Insulin Attenuates the Long-Term Adverse Effects of Neonatal Hyperglycemia on the Hippocampus in Rats

Hyperglycemia due to relative hypoinsulinism is common in extremely preterm infants and is associated with hippocampus-mediated long-term cognitive impairment. In neonatal rats, hypoinsulinemic hyperglycemia leads to oxidative stress, altered neurochemistry, microgliosis, and abnormal synaptogenesis in the hippocampus. Intranasal insulin (INS) bypasses the blood-brain barrier, targets the brain, and improves synaptogenesis in rodent models, and memory in adult humans with Alzheimer’s disease or type 2 diabetes, without altering the blood levels of insulin or glucose. To test whether INS improves hippocampal development in neonatal hyperglycemia, rat pups were subjected to hypoinsulinemic hyperglycemia by injecting streptozotocin (STZ) at a dose of 80 mg/kg i.p. on postnatal day (P) 2 and randomized to INS, 0.3U twice daily from P3-P6 (STZ + INS group), or no treatment (STZ group). The acute effects on hippocampal neurochemical profile and transcript mRNA expression of insulin receptor (Insr), glucose transporters (Glut1, Glut4, and Glut8), and poly(ADP-ribose) polymerase-1 (Parp1, a marker of oxidative stress) were determined on P7 using in vivo ¹H MR spectroscopy (MRS) and qPCR. The long-term effects on the neurochemical profile, microgliosis, and synaptogenesis were determined at adulthood using ¹H MRS and histochemical analysis. Relative to the control (CONT) group, mean blood glucose concentration was higher from P3 to P6 in the STZ and STZ + INS groups. On P7, MRS showed 10% higher taurine concentration in both STZ groups. qPCR showed 3-folds higher Insr and 5-folds higher Glut8 expression in the two STZ groups. Parp1 expression was 18% higher in the STZ group and normal in the STZ + INS group. At adulthood, blood glucose concentration in the fed state was higher in the STZ and STZ + INS groups. MRS showed 59% higher brain glucose concentration and histochemistry showed microgliosis in the hippocampal subareas in the STZ group. Brain glucose was normal in the STZ + INS group. Compared with the STZ group, phosphocreatine and phosphocreatine/creatine ratio were higher, and microglia in the hippocampal subareas fewer in the STZ + INS group (p < 0.05 for all). Neonatal hyperglycemia was associated with abnormal glucose metabolism and microgliosis in the adult hippocampus. INS administration during hyperglycemia attenuated these adverse effects and improved energy metabolism in the hippocampus.

Proton magnetic resonance spectroscopy assessment of neonatal brain metabolism during cardiopulmonary bypass surgery.

Here, we report on the development and performance of a robust 3-T single-voxel proton magnetic resonance spectroscopy (1 H MRS) experimental protocol and data analysis pipeline for quantifying brain metabolism during cardiopulmonary bypass (CPB) surgery in a neonatal porcine model, with the overall goal of elucidating primary mechanisms of brain injury associated with these procedures. The specific aims were to assess which metabolic processes can be reliably interrogated by 1 H MRS on a 3-T clinical scanner and to provide an initial assessment of brain metabolism during deep hypothermia cardiac arrest (DHCA) surgery and recovery. Fourteen neonatal pigs underwent CPB surgery while placed in a 3-T MRI scanner for 18, 28, and 37°C DHCA studies under hyperglycemic, euglycemic, and hypoglycemic conditions. Total imaging times, including baseline measurements, circulatory arrest (CA), and recovery averaged 3h/animal, during which 30-40 single-voxel 1 H MRS spectra (sLASER pulse sequence, TR/TE = 2000/30 ms, 64 or 128 averages) were acquired from a 2.2-cc right midbrain voxel. 1 H MRS at 3T was able to reliably quantify (1) anaerobic metabolism via depletion of brain glucose and the associated build-up of lactate during CA, (2) phosphocreatine (PCr) to creatine (Cr) conversion during CA and subsequent recovery upon reperfusion, (3) a robust increase in the glutamine-to-glutamate (Gln/Glu) ratio during the post-CA recovery period, and (4) a broadening of the water peak during CA. In vivo 1 H MRS at 3T can reliably quantify subtle metabolic brain changes previously deemed challenging to interrogate, including brain glucose concentrations even under hypoglycemic conditions, ATP usage via the conversion of PCr to Cr, and differential changes in Glu and Gln. Observed metabolic changes during CPB surgery of a neonatal porcine model provide new insights into possible mechanisms for prevention of neuronal injury.

Effect of diphenhydramine and phenobarbital in the concentration of glutathione and malondialdehyde and glucose in plasma and brain of chicks treated with pentylenetetrazol

Effect of diphenhydramine and phenobarbital in the concentration of glutathione and malondialdehyde and glucose in plasma and brain of chicks treated with pentylenetetrazol

228-OR: Cerebral Glucose Transport and Metabolism in Obesity

Metabolic derangement triggered by a high fat diet has been associated with decreased brain glucose uptake in mice through downregulation of GLUT-1 expression at the blood-brain barrier. Likewise, a prior study by our group using 1H magnetic resonance spectroscopy (MRS) showed diminished change in brain glucose level during acute hyperglycemia in patients with obesity and diabetes. However, whether this reflected differences in absolute brain concentrations remains unknown. We utilized 13C MRS scanning at 4 Tesla to compare the rate of glucose transport (Tmax) and cerebral metabolic rate of glucose (CMRgl) in the occipital lobe during a 2-hour hyperglycemic clamp. Plasma glucose concentration of ∼180mg/dl was achieved using a variable 1-13C-glucose infusion. The study included 8 healthy lean (1M/7F, age 29 ± 5 years, BMI 21 ± 2 kg/m2, HgbA1c 5.4 ± 0.2%) and 6 obese participants (4M/2F, age 30 ± 3 years, BMI 33 ± 3 kg/m2, HgbA1c 5.5 ± 0.2%). Insulin and free fatty acids (FFA) levels were measured during the clamp. Despite nearly identical plasma glucose concentrations at steady state (lean 182.5 ± 9.0 mg/dL, obese 186.5 ± 13.5 mg/dL, P=0.55, averaged over time 60-120 minutes), the absolute brain glucose concentrations were 30% less in obese compared to lean participants (P=0.02). Moreover, using previously reported Michaelis-Menten Kt of 1.1 mM, the calculated Tmax/CMRgl at steady state were 37% less in obese participants (P=0.01), suggesting reduced glucose transport. A trend of higher insulin and FFA levels in obese participants during hyperglycemia was observed. In addition, FFA levels at steady state were negatively correlated with absolute brain glucose concentrations (r= -0.575, P=0.05). We conclude that obesity is associated with diminished absolute concentration of brain glucose during acute hyperglycemia, likely explained by reduced cerebral glucose transport capacity. These findings may have implications for understanding the impact of obesity on central regulation of feeding behavior as well as neurocognitive function. Disclosure F. Gunawan: None. L. Jiang: None. J. Leventhal: None. J.J. Pach: None. E. Sanchez Rangel: None. R. Belfort-DeAguiar: Research Support; Self; Silver Palate Kitchens, Inc. A. Coppoli: None. D.L. Rothman: None. R. Sherwin: Other Relationship; Self; ICON plc., IQVIA, MannKind Corporation. G.F. Mason: None. J.J. Hwang: None. Funding American Diabetes Association (1-17-ICTS-013 to J.J.H.)

Co-administration of nicotine ameliorates cannabis-induced behavioral deficits in normal rats: role of oxidative stress and inflammation

Nicotine (Nic) and cannabis are considered to be the most abused drugs worldwide that are progressively taken concomitantly. The present study aimed to investigate the modulatory effect of Nic on cannabis extract–induced neuro-inflammation, oxidative status, and the associated behavioral/biochemical alterations. Nic (0.25 mg/kg) and/or cannabis extract expressed as ∆9-tetrahydrocannabinol (THC10/20; 10 and 20 mg/kg) were given intraperitoneally for 30 days to Wistar rats. Nic shortened the floating time in forced swimming test, increased locomotion in the open field test, and decreased escape latency in the Morris water maze when co-administered with THC. These effects were associated with the inhibition of THC-mediated elevations in brain interleukin-1 beta, lipid peroxidation, superoxide dismutase, and ascorbic acid. Additionally, Nic increased serum butyrylcholinesterase (BChE) when combined with THC without affecting the serum acetylcholinesterase enzyme. The combinations spiked the brain glucose content above normal. In conclusion, the co-administration of Nic reduced THC-induced depressive-like behavior and memory impairment as well as hypo-locomotion associated with THC20. Such effects could be linked to Nic-mediated inhibition of brain oxidative stress, inflammation, and decreased serum BChE deactivity.

Hypothalamic Glucose Concentrations Are Higher in Subjects with Type 1 Diabetes (T1D) and Impaired Awareness of Glycemia (IAH) than in T1D without IAH

IAH occurs commonly in patients with T1D but its pathogenesis remains uncertain. Previous investigation has suggested that recurrent hypoglycemia leads to an upregulation of brain glucose transport thereby assuring that the brain will have better fuel delivery during subsequent episodes of hypoglycemia. If so, subjects with T1D and IAH should have higher hypothalamic brain glucose concentrations than subjects with T1D without IHA when studied at the same level of glycemia. Here we used 1H-magnetic resonance spectroscopy at 7 T to measure (Glucose+Taurine)/ total Creatine in a 13x12x10 mm3 hypothalamic voxel in such patient groups while they were maintained at euglycemia and then hypoglycemia using a glucose clamp. Since taurine and creatine do not change with glycemia, this is a valid measure of brain glucose concentrations. IAH was defined using the Clarke questionnaire with subjects found indeterminate further classified using the Gold questionnaire. We found that hypothalamic (Glucose+Taurine)/ total Creatine was significantly higher in T1D with IAH at both euglycemia and hypoglycemia when compared to T1D without IAH. These data support the hypothesis that a change in glucose transport may contribute to the pathogenesis of IAH. T1D with IAH (n=9)T1D without IAH (n=9)Age (years)47.6 ± 1729.2 ± 8Hemoglobin A1c (%)7.3 ± 0.97.3 ± 0.7Glycemia at euglycemia (mg/dl)98 ± 495 ± 7Glycemia during hypoglycemia (mg/dl)48 ± 348 ± 5Epinephrine during hypoglycemia (pg/ml)250 ± 155711±442*Symptom score during hypoglycemia8 ± 936 ± 14**Hypothalamic glucose at euglycemia (Glucose+Taurine)/ total Creatine (mM)0.43 ± 0.110.27 ± 0.08**Hypothalamic glucose at hypoglycemia (Glucose+Taurine)/ total Creatine (mM)0.23 ± 0.040.15 ± 0.02***p=0.03, **p &amp;lt; 0.001. Disclosure A. Moheet: None. D. Deelchand: None. A. Kumar: None. G. Oz: Research Support; Self; Takeda Pharmaceuticals U.S.A., Inc. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..

Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse.

Insulin delivery to the brain has emerged as an important therapeutic target for cognitive disorders associated with abnormal brain energy metabolism. Although insulin is transported across the blood-brain barrier, peripheral routes of administration are problematic due to systemic effects of insulin on blood glucose. Intranasal (IN) administration is being investigated as an alternative route. We conducted a head-to-head comparison of subcutaneous (SC) and IN insulin, assessing plasma and brain pharmacokinetics and blood glucose levels in the mouse. SC insulin (2.4 IU) achieved therapeutically relevant concentrations in the brain (AUCbrain = 2537 h·μIU/mL) but dramatically increased plasma insulin (AUCplasma = 520 351 h·*μIU/mL), resulting in severe hypoglycemia and in some cases death. IN administration of the same dose resulted in similar insulin levels in the brain (AUCbrain = 3442 h·μIU/mL) but substantially lower plasma concentrations (AUCplasma = 354 h·μIU/mL), amounting to a ∼ 2000-fold increase in the AUCbrain:plasma ratio relative to SC. IN dosing also had no significant effect on blood glucose. When administered daily for 9 days, IN insulin increased brain glucose and energy metabolite concentrations (e.g., adenosine triphosphate and phosphocreatine) without causing overt toxicity, suggesting that IN insulin may be a safe therapeutic option for cognitively impaired patients.

Evidence for brain glucose dysregulation in Alzheimer's disease

IntroductionIt is unclear whether abnormalities in brain glucose homeostasis are associated with Alzheimer's disease (AD) pathogenesis. MethodsWithin the autopsy cohort of the Baltimore Longitudinal Study of Aging, we measured brain glucose concentration and assessed the ratios of the glycolytic amino acids, serine, glycine, and alanine to glucose. We also quantified protein levels of the neuronal (GLUT3) and astrocytic (GLUT1) glucose transporters. Finally, we assessed the relationships between plasma glucose measured before death and brain tissue glucose. ResultsHigher brain tissue glucose concentration, reduced glycolytic flux, and lower GLUT3 are related to severity of AD pathology and the expression of AD symptoms. Longitudinal increases in fasting plasma glucose levels are associated with higher brain tissue glucose concentrations. DiscussionImpaired glucose metabolism due to reduced glycolytic flux may be intrinsic to AD pathogenesis. Abnormalities in brain glucose homeostasis may begin several years before the onset of clinical symptoms.

Maternal Glucose Supplementation in a Murine Model of Chorioamnionitis Alleviates Dysregulation of Autophagy in Fetal Brain.

Fetal brain injury induced by intrauterine inflammation is a major risk factor for adverse neurological outcomes, including cerebral palsy, cognitive dysfunction, and behavioral disabilities. There are no adequate therapies for neuronal protection to reduce fetal brain injury, especially new strategies that may apply promptly and conveniently. In this study, we explored the effect of maternal glucose administration in a mouse model of intrauterine inflammation at term. Our results demonstrated that maternal glucose supplementation significantly increased survival birth rate and improved the neurobehavioral performance of pups exposed to intrauterine inflammation. Furthermore, we demonstrated that maternal glucose administration improved myelination and oligodendrocyte development in offspring exposed to intrauterine inflammation. Though the maternal blood glucose concentration was temporally prevented from decrease induced by intrauterine inflammation, the glucose concentration in fetal brain was not recovered by maternal glucose supplementation. The adenosine triphosphate (ATP) level and autophagy in fetal brain were regulated by maternal glucose supplementation, which may prevent dysregulation of cellular metabolism. Our study is the first to provide evidence for the role of maternal glucose supplementation in the cell survival of fetal brain during intrauterine inflammation and further support the possible medication with maternal glucose treatment.

Dissociation Between Hormonal Counterregulatory Responses and Cerebral Glucose Metabolism During Hypoglycemia.

Hypoglycemia is the most common complication of diabetes, causing morbidity and death. Recurrent hypoglycemia alters the cascade of physiological and behavioral responses that maintain euglycemia. The extent to which these responses are normally triggered by decreased whole-brain cerebral glucose metabolism (CMRglc) has not been resolved by previous studies. We measured plasma counterregulatory hormonal responses and whole-brain CMRglc (along with blood-to-brain glucose transport rates and brain glucose concentrations) with 1-[11C]-d-glucose positron emission tomography during hyperinsulinemic glucose clamps at nominal plasma glucose concentrations of 90, 75, 60, and 45 mg/dL (5.0, 4.2, 3.3, and 2.5 mmol/L) in 18 healthy young adults. Clear evidence of hypoglycemic physiological counterregulation was first demonstrated between 75 mg/dL (4.2 mmol/L) and 60 mg/dL (3.3 mmol/L) with increases in both plasma epinephrine (P = 0.01) and glucagon (P = 0.01). In contrast, there was no statistically significant change in CMRglc (P = 1.0) between 75 mg/dL (4.2 mmol/L) and 60 mg/dL (3.3 mmol/L), whereas CMRglc significantly decreased (P = 0.02) between 60 mg/dL (3.3 mmol/L) and 45 mg/dL (2.5 mmol/L). Therefore, the increased epinephrine and glucagon secretion with declining plasma glucose concentrations is not in response to a decrease in whole-brain CMRglc.

Epigenetic regulation of the glucose transporter gene Slc2a1 by β-hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice.

We carried out liquid chromatography-tandem mass spectrometry analysis of metabolites in mice. Those metabolome data showed that hepatic glucose content is reduced, but that brain glucose content is unaffected, during fasting, consistent with the priority given to brain glucose consumption during fasting. The molecular mechanisms for this preferential glucose supply to the brain are not fully understood. We also showed that the fasting-induced production of the ketone body β-hydroxybutyrate (β-OHB) enhances expression of the glucose transporter gene Slc2a1 (Glut1) via histone modification. Upon β-OHB treatment, Slc2a1 expression was up-regulated, with a concomitant increase in H3K9 acetylation at the critical cis-regulatory region of the Slc2a1 gene in brain microvascular endothelial cells and NB2a neuronal cells, shown by quantitative PCR analysis and chromatin immunoprecipitation assay. CRISPR/Cas9-mediated disruption of the Hdac2 gene increased Slc2a1 expression, suggesting that it is one of the responsible histone deacetylases (HDACs). These results confirm that β-OHB is a HDAC inhibitor and show that β-OHB plays an important role in fasting-induced epigenetic activation of a glucose transporter gene in the brain.

Detection of glucose in the human brain with 1 H MRS at 7 Tesla.

A new method is proposed for noninvasive detection of glucose in vivo using proton MR spectroscopy at 7 Tesla. The proposed method utilizes J-difference editing to uncover the resonance of beta-glucose (β-glc) at 3.23 ppm, which is strongly overlapped with choline. Calculations using the density matrix formalism are used to maximize the signal-to-noise ratio of the β-glc resonance at 3.23 ppm. The calculations are verified using phantom and in vivo data collected at 7 Tesla. The proposed method allows observation of the glucose signal at 3.23 ppm in the human brain spectrum. Additional co-edited resonances of N-acetylaspartylglutamatate and glutathione are also detected in the same experiment. The proposed method does not require carbon (13 C)- labeled glucose injections and 13 C hardware; as such, it has a potential to provide valuable information on intrinsic glucose concentration in the human brain in vivo. Magn Reson Med 76:1653-1660, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Altered hypermetabolic response to cortical spreading depolarizations after traumatic brain injury in rats

Spreading depolarizations are waves of near-complete breakdown of neuronal transmembrane ion gradients, free energy starving, and mass depolarization. Spreading depolarizations in electrically inactive tissue are associated with poor outcome in patients with traumatic brain injury. Here, we studied changes in regional cerebral blood flow and brain oxygen (PbtO2), glucose ([Glc]b), and lactate ([Lac]b) concentrations in rats, using minimally invasive real-time sensors. Rats underwent either spreading depolarizations chemically triggered by KCl in naïve cortex in absence of traumatic brain injury or spontaneous spreading depolarizations in the traumatic penumbra after traumatic brain injury, or a cluster of spreading depolarizations triggered chemically by KCl in a remote window from which spreading depolarizations invaded penumbral tissue. Spreading depolarizations in noninjured cortex induced a hypermetabolic response characterized by a decline in [Glc]b and monophasic increases in regional cerebral blood flow, PbtO2, and [Lac]b, indicating transient hyperglycolysis. Following traumatic brain injury, spontaneous spreading depolarizations occurred, causing further decline in [Glc]b and reducing the increase in regional cerebral blood flow and biphasic responses of PbtO2 and [Lac]b, followed by prolonged decline. Recovery of PbtO2 and [Lac]b was significantly delayed in traumatized animals. Prespreading depolarization [Glc]b levels determined the metabolic response to clusters. The results suggest a compromised hypermetabolic response to spreading depolarizations and slower return to physiological conditions following traumatic brain injury-induced spreading depolarizations.

Intracerebral hypoglycemia and its clinical relevance as a prognostic indicator in severe traumatic brain injury: A cerebral microdialysis study from India.

Traumatic brain injury (TBI) remains a major cause of morbidity and mortality worldwide. Largely, the prognosis is dependent on the nonmodifiable factors such as severity of the initial injury, Glasgow coma scale score, pupillary response, age, and presence of additional physiological derangements such as hypoxia or hypotension. However, secondary insults continue to take place after the initial injury and resuscitation. The study hypothesis in the present research article was that hypoglycemia is an independent outcome prognosticator in severe traumatic brain injury. The study aimed to assess the role of glucose monitoring in the brain parenchyma as an independent outcome prognosticator and also to study its association with plasma glucose levels. The aim of the study was to analyze the relationship of intracerebral glucose measured by intraparenchymal cerebral microdialysis (CMD), and also to study its relationship with blood glucose levels. We also evaluated the relationship of these values to the outcome of patients. Prospective nonrandomized study conducted at a tertiary care trauma center in India. Twenty-five patients with severe TBI, who underwent decompressive craniectomy, were prospectively monitored with CMD catheters. Twenty cases had unilateral catheters placed intraparenchymally (20 mm inside the brain parenchyma to accommodate 10 mm of the semipermeable catheter tip and another 10 mm of extra catheter length). Frontotemporal contusions were noted in 21 cases and an acute subdural hematoma (with/without associated contusions) were noted in 15 cases in the present series. Bilateral CMD catheters were placed during bifrontal decompressive craniectomies in five patients (two patients had peri-contusional catheters placement; these patients had bilateral frontal contusions); while, the remaining 3 patients had a contralateral catheter placement in the normal brain parenchyma [Table 1]. The position of the catheters was confirmed on postoperative computerized tomographic scan carried out in these subjects. However, bilateral catheter placement to compare the difference in cerebral biochemical values of glucose in the penumbric zone as well as the normal brain could not be done in all cases due to cost restraints. The relation between plasma glucose and CMD-measured interstitial brain glucose concentrations, as well as the temporal pattern of CMD glucose was studied for 3-5 days following a decompressive craniectomy using a CMD analyzer at the patient's bedside at 1 hourly intervals. All data were tabulated in Microsoft Excel 2011 and analyzed using SPSS version 21. To calculate the correlation between plasma and CMD glucose, Pearson's correlation was used with a two-tailed test of significance. Student's t-test was used to calculate the difference in means between the two groups. Significance was assumed at P ≤ 0.05. Fifteen patients (60%) had a good outcome in terms of the Glasgow Outcome Scale (GOS) at 3 months while the rest (10 patients) had a poor GOS at 3 months. There was a significant difference in the incidence of hyperglycemia (random blood sugar >10 mmol/L) between the two groups (P < 0.0001). The difference between the two groups while comparing episodes of hypoglycemia was also significant (P = 0.0026). The good outcome group had fewer episodes of brain hypoglycemia during the presence of systemic hypoglycemia (P = 0.0026). Neither the mean blood glucose values nor the mean cerebral glucose values predicted the outcome at 3 months. After decompressive craniectomy in severe TBI, there was a poor correlation between the plasma and CMD glucose concentration. A higher degree of variation was seen in the correlations for individual patients. Neither the mean blood glucose values nor the mean cerebral glucose values predicted the outcome at 3 months. The good outcome group had fewer episodes of both hyperglycemia and hypoglycemia.

A comparison between the impact of two types of dietary protein on brain glucose concentrations and oxidative stress in high fructose-induced metabolic syndrome rats.

The present study explored the potential of fish proteins to counteract high glucose levels and oxidative stress induced by fructose in the brain. A total of 24 male Wistar rats consumed sardine protein or casein with or without high fructose (64%). After 2 months, brain tissue was used for analyses. The fructose rats exhibited an increase in body mass index (BMI), body weight, absolute and relative brain weights and brain glucose; however, there was a decrease in food and water intake. Fructose disrupts membrane homeostasis, as evidenced by an increase in the brain hydroperoxides and a decrease in catalase (CAT) and glutathione peroxidase (GSH-Px) compared to the control. The exposure to the sardine protein reduced BMI, food intake, glucose and hydroperoxides, and increased CAT and GSH-Px in the brain. In conclusion, the metabolic dysfunctions associated with the fructose treatment were ameliorated by the presence of sardine protein in the diet by decreasing BMI, brain glucose and lipid peroxidation, and increasing CAT and GSH-Px activities.

Mechanisms linking depression co-morbid with obesity: An approach for serotonergic type 3 receptor antagonist as novel therapeutic intervention.

Despite of the enormous research, therapeutic treatment for depression has always been a serious issue. Even though depression and obesity are individual abnormal health conditions, each act as a triggering factor for the other. Obese individuals are twice prone to develop depression than that of non-obese persons. The exact mechanism how obesity increases the risk for depression still remains an area of interest for research in neuropsychopharmacology. Depression and obesity share some common pathological pathways such as hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, dysregulation of oxidant/antioxidant system balance, higher level of inflammatory cytokines, leptin resistance, altered plasma glucose, insulin resistance, reduced neuronal brain derived neurotrophic factor (BDNF) and decreased serotonergic neurotransmission in various regions of brain. The antidepressant-like effect of 5-HT3 receptor antagonists through allosteric modulation of serotonergic pathways is well evident from several research investigations belonging to our and some in other laboratories. Furthermore, serotonin regulates diet intake, leptin, corticosterone, inflammatory mechanisms, altered plasma glucose, insulin resistance and BDNF concentration in brain. The present review deals with various biological mechanisms involved in depression co-morbid with obesity and 5-HT3 receptor antagonists by modulation of serotonergic system as a therapeutic target for such co-morbid disorder.

Cerebral Glucose Metabolism and Sedation in Brain-injured Patients: A Microdialysis Study.

Disturbed brain metabolism is a signature of primary damage and/or precipitates secondary injury processes after severe brain injury. Sedatives and analgesics target electrophysiological functioning and are as such well-known modulators of brain energy metabolism. Still unclear, however, is how sedatives impact glucose metabolism and whether they differentially influence brain metabolism in normally active, healthy brain and critically impaired, injured brain. We therefore examined and compared the effects of anesthetic drugs under both critical (<1 mmol/L) and noncritical (>1 mmol/L) extracellular brain glucose levels. We performed an explorative, retrospective analysis of anesthetic drug administration and brain glucose concentrations, obtained by bedside microdialysis, in 19 brain-injured patients. Our investigations revealed an inverse linear correlation between brain glucose and both the concentration of extracellular glutamate (Pearson r=-0.58, P=0.01) and the lactate/glucose ratio (Pearson r=-0.55, P=0.01). For noncritical brain glucose levels, we observed a positive linear correlation between midazolam dose and brain glucose (P<0.05). For critical brain glucose levels, extracellular brain glucose was unaffected by any type of sedative. These findings suggest that the use of anesthetic drugs may be of limited value in attempts to influence brain glucose metabolism in injured brain tissue.

Neuronal LRP1 Regulates Glucose Metabolism and Insulin Signaling in the Brain

Alzheimer's disease (AD) is a neurological disorder characterized by profound memory loss and progressive dementia. Accumulating evidence suggests that Type 2 diabetes mellitus, a metabolic disorder characterized by insulin resistance and glucose intolerance, significantly increases the risk for developing AD. Whereas amyloid-β (Aβ) deposition and neurofibrillary tangles are major histological hallmarks of AD, impairment of cerebral glucose metabolism precedes these pathological changes during the early stage of AD and likely triggers or exacerbates AD pathology. However, the mechanisms linking disturbed insulin signaling/glucose metabolism and AD pathogenesis remain unclear. The low-density lipoprotein receptor-related protein 1 (LRP1), a major apolipoprotein E receptor, plays critical roles in lipoprotein metabolism, synaptic maintenance, and clearance of Aβ in the brain. Here, we demonstrate that LRP1 interacts with the insulin receptor β in the brain and regulates insulin signaling and glucose uptake. LRP1 deficiency in neurons leads to impaired insulin signaling as well as reduced levels of glucose transporters GLUT3 and GLUT4. Consequently, glucose uptake is reduced. By using an in vivo microdialysis technique sampling brain glucose concentration in freely moving mice, we further show that LRP1 deficiency in conditional knock-out mice resulted in glucose intolerance in the brain. We also found that hyperglycemia suppresses LRP1 expression, which further exacerbates insulin resistance, glucose intolerance, and AD pathology. As loss of LRP1 expression is seen in AD brains, our study provides novel insights into insulin resistance in AD. Our work also establishes new targets that can be explored for AD prevention or therapy.

Brain functioning under acute hypothermic stress supported by dynamic monocarboxylate utilization and transport in ectothermic fish

BackgroundThe vertebrate brain is a highly energy consuming organ that requires continuous energy provision. Energy metabolism of ectothermic organisms is directly affected by environmental temperature changes and has been demonstrated to affect brain energy balance in fish. Fish were hypothesized to metabolize lactate as an additional energy substrate during acute exposure to energy demanding environmental abiotic fluctuations to support brain functionality. However, to date the pathways of lactate mobilization and transport in the fish brain are not well understood, and may represent a critical physiological feature in ectotherms during acclimation to low temperature.ResultsWe found depressed routine metabolic rates in zebrafish during acute exposure to hypothermic (18°C) conditions accompanied by decreased lactate concentrations in brain tissues. No changes in brain glucose content were observed. Acute cold stress increased protein concentrations of lactate dehydrogenase 1 (LDH1) and citrate synthase (CS) in brain by 1.8- and- 2.5-fold, paralleled by an increased pyruvate to acetyl-CoA transformation. To test the involvement of monocarboxylate transporters (MCTs) under acute cold stress in zebrafish, we cloned and sequenced seven MCT1-4 homologues in zebrafish. All drMCT1-4 are expressed in brain tissues and in response to cold stress drmct2a and drmct4a transcripts were up-regulated 5- and 3-fold, respectively. On the contrary, mRNA levels of drmct1a, -1b and -4b in zebrafish brain responded with a down regulation in response to cold stress. By expressing drMCTs in Xenopus oocytes we could provide functional evidence that hypothermic stress leads to a 2-fold increase in lactate transport in drMCT4b expressing oocytes. Lactate transport of other paralogues expressed in oocytes was unaffected, or even decreased during cold stress.ConclusionThe present work provides evidence that lactate utilization and transport pathways represent an important energy homeostatic feature to maintain vital functions of brain cells during acute cold stress in ectotherms.