Brain Glucose Transport Research Articles

Neurodevelopment Is Dependent on Maternal Diet: Placenta and Brain Glucose Transporters GLUT1 and GLUT3.

Glucose is the primary energy source for most mammalian cells and its transport is affected by a family of facilitative glucose transporters (GLUTs) encoded by the SLC2 gene. GLUT1 and GLUT3, highly expressed isoforms in the blood-brain barrier and neuronal membranes, respectively, are associated with multiple neurodevelopmental disorders including epilepsy, dyslexia, ADHD, and autism spectrum disorder (ASD). Dietary therapies, such as the ketogenic diet, are widely accepted treatments for patients with the GLUT1 deficiency syndrome, while ameliorating certain symptoms associated with GLUT3 deficiency in animal models. A ketogenic diet, high-fat diet, and calorie/energy restriction during prenatal and postnatal stages can also alter the placental and brain GLUTs expression with long-term consequences on neurobehavior. This review focuses primarily on the role of diet/energy perturbations upon GLUT isoform-mediated emergence of neurodevelopmental and neurodegenerative disorders.

Deficits in brain glucose transport among younger adults with obesity.

Obesity is associated with alterations in eating behavior and neurocognitive function. In this study, we investigate the effect of obesity on brain energy utilization, including brain glucose transport and metabolism. A total of 11 lean participants and 7 young healthy participants with obesity (mean age, 27 years) underwent magnetic resonance spectroscopy scanning coupled with a hyperglycemic clamp (target, ~180 mg/dL) using [1-13C] glucose to measure brain glucose uptake and metabolism, as well as peripheral markers of insulin resistance. Individuals with obesity demonstrated an ~20% lower ratio of brain glucose uptake to cerebral glucose metabolic rate (Tmax/CMRglucose) than lean participants (2.12 ± 0.51 vs. 2.67 ± 0.51; p = 0.04). The cerebral tricarboxylic acid cycle flux (VTCA) was similar between the two groups (p = 0.64). There was a negative correlation between total nonesterified fatty acids and Tmax/CMRglucose (r = -0.477; p = 0.045). We conclude that CMRglucose is unlikely to differ between groups due to similar VTCA, and, therefore, the glucose transport Tmax is lower in individuals with obesity. These human findings suggest that obesity is associated with reduced cerebral glucose transport capacity even at a young age and in the absence of other cardiometabolic comorbidities, which may have implications for long-term brain function and health.

Cerebral Glucose Metabolism following TBI: Changes in Plasma Glucose, Glucose Transport and Alternative Pathways of Glycolysis-A Translational Narrative Review.

Traumatic brain injury (TBI) is a major public health concern with significant consequences across various domains. Following the primary event, secondary injuries compound the outcome after TBI, with disrupted glucose metabolism emerging as a relevant factor. This narrative review summarises the existing literature on post-TBI alterations in glucose metabolism. After TBI, the brain undergoes dynamic changes in brain glucose transport, including alterations in glucose transporters and kinetics, and disruptions in the blood-brain barrier (BBB). In addition, cerebral glucose metabolism transitions from a phase of hyperglycolysis to hypometabolism, with upregulation of alternative pathways of glycolysis. Future research should further explore optimal, and possibly personalised, glycaemic control targets in TBI patients, with GLP-1 analogues as promising therapeutic candidates. Furthermore, a more fundamental understanding of alterations in the activation of various pathways, such as the polyol and lactate pathway, could hold the key to improving outcomes following TBI.

Reduced Blood to Brain Glucose Transport as the Cause for Hyperglycemia: A Model That Resolves Multiple Anomalies in Type 2 Diabetes

Classically type 2 diabetes is believed to be a result of insulin resistance and relative insulin deficiency. However, evidences have been accumulating against the insulin resistance models. Absence of lasting hyperglycemia by insulin receptor knockouts or insulin suppression, evidence for hyperinsulinemia preceding insulin resistance, the perplexing hyperinsulinemic normoglycemic state, reduced glucose transport to the brain preceding hyperglycemia, signs of vasculopathy preceding hyperglycemia, absent or poor correlation between fasting glucose and insulin, very strong positive correlation between indices of insulin resistance and β cell function in population data are some of the anomalous findings which classical glucose homeostasis models have not addressed so far. With increasing evidence for neuronal involvement in glucose regulation, we propose a refined model of glucose regulation that considers brain glucose and insulin levels as the ultimate target of homeostasis and combines central and peripheral mechanisms of regulation. A model considering reduced rate of blood to brain transportation of glucose and insulin as primary pathology explains most of the patterns, with or without insulin resistance or any other defect in glucose regulation mechanisms. Apart from resolving multiple anomalies the model also accounts for the failure of glucose normalization in effectively reducing diabetic complications and mortality.

Reduced Blood to Brain Glucose Transport as The Cause For Hyperglycemia: a Model That Resolves Multiple Anomalies in Type 2 Diabetes

Classically, type 2 diabetes is believed to be a result of insulin resistance and relative insulin deficiency. However, evidence has been accumulating against the insulin resistance models. Absence of lasting hyperglycemia by insulin receptor knockouts or insulin suppression, evidence for hyperinsulinemia preceding insulin resistance, the perplexing hyperinsulinemic normoglycemic state, reduced glucose transport to the brain preceding hyperglycemia, signs of vasculopathy preceding hyperglycemia, absent or poor correlation between fasting glucose and insulin, very strong positive correlation between indices of insulin resistance and β cell function in population data are some of the anomalous findings which classical glucose homeostasis models have not addressed so far. With increasing evidence for neuronal involvement in glucose regulation, we propose a refined model of glucose regulation that considers brain glucose and insulin levels as the ultimate target of homeostasis and combines central and peripheral mechanisms of regulation. A model considering the reduced rate of blood-to-brain transportation of glucose and insulin as primary pathology explains most of the patterns, with or without insulin resistance. Apart from resolving multiple anomalies, the model also accounts for the failure of glucose normalization in effectively reducing diabetic complications and mortality.

Menopause and development of Alzheimer's disease: Roles of neural glucose metabolism and Wnt signaling.

Late onset Alzheimer´s disease (AD) is a neurodegenerative disease with gender differences in its onset and progression, being the prevalence predominant in women and at an earlier age than in men. The pathophysiology of the menopausal condition has been associated to this dementia, playing major roles regarding both endocrine and glucose metabolism changes, amongst other mechanisms. In the current review we address the role of estrogen deficiency in the processes involved in the development of AD, including amyloid precursor protein (APP) processing to form senile plaques, Tau phosphorylation forming neurofibrillary tangles, Wnt signaling and AD neuropathology, the role of glucose brain metabolism, Wnt signaling and glucose transport in the brain, and our research contribution to these topics.

Conjugated linoleic acid downregulates Alzheimer's hallmarks in aluminum mouse model through an Nrf2-mediated adaptive response and increases brain glucose transporter levels.

Mitochondrial dysfunction, oxidative stress, inflammation and glucose dysmetabolism are pathological signs of Alzheimer's disease (AD). Dietary aluminum (Al) overload is often used to induce AD in rodents and trigger the onset of oxidative-stress hallmarks resembling those of the human disease. The Nuclear factor erythroid 2-related factor 2 (Nrf2), owing to its key role in redox homeostasis, mitochondrial function and inflammation, is a promising drug target for neurological disorders, but only a few data are available on its modulatory effects on glucose transporter expression levels. While it has been found that the protective effect of Conjugated linoleic acid (CLA) occurs through the activation of an Nrf2-mediated adaptive response, its beneficial effect on the considered pathological signs in the Al-induced model has not been established yet. Thirty-five male BalbC mice were divided into 5 groups: two Al-intoxicated groups were treated for 5 weeks with low or high Al doses (8 or 100mg/kg/day in drinking water, respectively; L or H). Two groups of animals, orally supplemented with CLA (600mg/kgbw/day) for 7 weeks (2 preliminary weeks plus the 5-week treatment with Al; CLA+L, CLA+H) were used to investigate its protective effect, while untreated mice were used as control (Cntr). We provide evidence that mitochondrial dysfunction, Nrf2 alteration, inflammation and Acetylcholinesterase (AChE) hyperactivation can occur even from L exposure. Interestingly, animal pre-treatment with an allometric CLA dose led to significant downregulation of the toxic effects elicited by L or H, likely through the activation of an adaptive response. In conclusion, CLA ability to increase the level of glucose transporters - along with its antioxidant and anti-inflammatory effect - expands the therapeutic targets of these molecules and comes out as an intriguing suitable candidate for the treatment of multifactorial disease.

Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice.

Icariin, a major prenylated flavonoid found in Epimedium spp., is a bioactive constituent of Herba Epimedii and has been shown to exert neuroprotective effects in experimental models of Alzheimer's disease. In this study, we investigated the neuroprotective mechanism of icariin in an APP/PS1/Tau triple-transgenic mouse model of Alzheimer's disease. We performed behavioral tests, pathological examination, and western blot assay, and found that memory deficits of the model mice were obviously improved, neuronal and synaptic damage in the cerebral cortex was substantially mitigated, and amyloid-β accumulation and tau hyperphosphorylation were considerably reduced after 5 months of intragastric administration of icariin at a dose of 60 mg/kg body weight per day. Furthermore, deficits of proteins in the insulin signaling pathway and their phosphorylation levels were significantly reversed, including the insulin receptor, insulin receptor substrate 1, phosphatidylinositol-3-kinase, protein kinase B, and glycogen synthase kinase 3β, and the levels of glucose transporter 1 and 3 were markedly increased. These findings suggest that icariin can improve learning and memory impairments in the mouse model of Alzheimer's disease by regulating brain insulin signaling and glucose transporters, which lays the foundation for potential clinical application of icariin in the prevention and treatment of Alzheimer's disease.

Central GLP-1 contributes to improved cognitive function and brain glucose uptake after duodenum-jejunum bypass on obese and diabetic rats.

The improvement of cognitive function following bariatric surgery has been highlighted, yet its underlying mechanisms remain elusive. Finding the improved brain glucose uptake of patients after Roux-en-Y gastric bypass (RYGB), duodenum-jejunum bypass (DJB), and sham surgery (Sham) were performed on obese and diabetic Wistar rats, and intracerebroventricular (ICV) injection of glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira), antagonist exendin-(9-39) (Exe-9), and the viral-mediated GLP-1 receptor (Glp-1r) knockdown (KD) were applied on both groups to elucidate the role of GLP-1 in mediating cognitive function and brain glucose uptake assessed with the Morris water maze (MWM) and positron emission tomography (PET). Insulin and GLP-1 in serum and cerebral spinal fluid (CSF) were measured, and the expression of glucose uptake-related proteins including glucose transporter 1 (GLUT-1), GLUT-4, phospho-Akt substrate of 160kDa (pAS160), AS160, Rab10, Myosin-Va as well as the c-fos marker in the brain were examined. Along with augmented glucose homeostasis following DJB, central GLP-1 was correlated with the improved cognitive function and ameliorated brain glucose uptake, which was further confirmed by the enhancive role of Lira on both groups whereas the Exe-9 and Glp-1r KD were opposite. Known to activate insulin-signaling pathways, central GLP-1 contributes to improved cognitive function and brain glucose uptake after DJB.NEW & NOTEWORTHY The improvement of cognitive function following bariatric surgery has been highlighted while its mechanisms remain elusive. The brain glucose uptake of patients was improved after RYGB, and the DJB and sham surgery performed on obese and diabetic Wistar rats revealed that the elevated central GLP-1 contributes to the dramatic improvement of cognitive function, brain glucose uptake, transport, glucose sensing, and neuronal activation.

Brain Glucose Transporters: Role in Pathogenesis and Potential Targets for the Treatment of Alzheimer's Disease.

The most common cause of dementia, especially in elderly people, is Alzheimer’s disease (AD), with aging as its main risk factor. AD is a multifactorial neurodegenerative disease. There are several factors increasing the risk of AD development. One of the main features of Alzheimer’s disease is impairment of brain energy. Hypometabolism caused by decreased glucose uptake is observed in specific areas of the AD-affected brain. Therefore, glucose hypometabolism and energy deficit are hallmarks of AD. There are several hypotheses that explain the role of glucose hypometabolism in AD, but data available on this subject are poor. Reduced transport of glucose into neurons may be related to decreased expression of glucose transporters in neurons and glia. On the other hand, glucose transporters may play a role as potential targets for the treatment of AD. Compounds such as antidiabetic drugs, agonists of SGLT1, insulin, siRNA and liposomes are suggested as therapeutics. Nevertheless, the suggested targets of therapy need further investigations.

Developing Brain Glucose Transporters, Serotonin, Serotonin Transporter, and Oxytocin Receptor Expression in Response to Early-Life Hypocaloric and Hypercaloric Dietary, and Air Pollutant Exposures

Perturbed maternal diet and prenatal exposure to air pollution (AP) affect the fetal brain, predisposing to postnatal neurobehavioral disorders. Glucose transporters (GLUTs) are key in fueling neurotransmission; deficiency of the neuronal isoform GLUT3 culminates in autism spectrum disorders. Along with the different neurotransmitters, serotonin (5-HT) and oxytocin (OXT) are critical for the development of neural connectivity. Serotonin transporter (SERT) modulates synaptic 5-HT levels, while the OXT receptor (OXTR) mediates OXT action. We hypothesized that perturbed brain GLUT1/GLUT3 regulated 5-HT-SERT imbalance, which serves as a contributing factor to postnatal neuropsychiatric phenotypes, with OXT/OXTR providing a counterbalance. Employing maternal diet restriction (intrauterine growth restriction [IUGR]), high-fat (HF) dietary modifications, and prenatal exposure to simulated AP, fetal (E19) murine brain 5-HT was assessed by ELISA with SERT and OXTR being localized by immunohistochemistry and measured by quantitative Western blot analysis. IUGR with lower head weights led to a 48% reduction in male and female fetal brain GLUT3 with no change in GLUT1, when compared to age- and sex-matched controls, with no significant change in OXTR. In addition, a ∼50% (p = 0.005) decrease in 5-HT and SERT concentrations was displayed in fetal IUGR brains. In contrast, despite emergence of microcephaly, exposure to a maternal HF diet or AP caused no significant changes. We conclude that in the IUGR during fetal brain development, reduced GLUT3 is associated with an imbalanced 5-HT-SERT axis. We speculate that these early changes may set the stage for altering the 5HT-SERT neural axis with postnatal emergence of associated neurodevelopmental disorders.

Kolaviron stimulates glucose uptake with concomitant modulation of metabolic activities implicated in neurodegeneration in isolated rat brain, without perturbation of tissue ultrastructural morphology

Reduced glucose uptake usually occurs in type 2 diabetes due to down-regulation of brain glucose transporters. The potential of kolaviron, a biflavonoid from Garcinia kola to stimulate glucose uptake and suppress glucose-induced oxidative toxicity were investigated in rat brain. Its molecular interactions with the target proteins were investigated in silico. Kolaviron was incubated with excised rat brain in the presence of glucose for 2 h, with metformin serving as a positive control. Kolaviron caused a significant (p < 0.05) increase in glucose uptake, glutathione level, superoxide dismutase, catalase, ATPase, ENTPDase and 5’-nucleotidase activities, while concomitantly depleting malondialdehyde level, acetylcholinesterase and butyrylcholinesterase activities compared to brains incubated with glucose only. Electron microscopy (SEM and TEM) analysis revealed kolaviron had little or no effect on the ultrastructural morphology of brain tissues as evidenced by the intact dendritic and neuronal network, blood vessels, mitochondria, synaptic vesicles, and pre-synaptic membrane. SEM-EDX analysis revealed a restorative effect of glucose-induced alteration in brain elemental concentrations, with total depletion of aluminum and zinc. MTT analysis revealed kolaviron had no cytotoxic effect on HT-22 cells. Molecular docking revealed a potent interaction between kolaviron and catalase at the SER114 and MET350 residues, with a binding energy of 12 kcal/mol. Taken together, these results portray the potential of kolaviron to stimulate glucose uptake while concomitantly coffering a neuroprotective effect.

Neuroprotective potential of antihyperglycemic drug metformin in streptozocin-induced rat model of sporadic Alzheimer's disease

The earliest hallmarks of sporadic Alzheimer's disease (sAD) are impaired glucose metabolism, chronic neuroinflammation, diminished synaptic plasticity and subsequent cognitive decline. The safest antidiabetic drug metformin has shown both glucose metabolism-improving and cognition-enhancing action in type 2 diabetes patients and diabetic model animals. However, metformin has not been previously studied in intracerebroventricular streptozocin (STZ)-induced model of sAD. Therefore, our aim was to assess the preventive action of metformin in sAD model-rats. Firstly, the actions of metformin (75 and 100 mg/kg) on cognitive functions and sociability were examined. Secondly, we wanted to identify whether behavioral effects of metformin were provided via its action on brain glucose transport, neuronal/glial uptake and metabolism. Thirdly, the effects of metformin on neuroinflammation, acetylcholine esterase density and activity, as well as on synaptic plasticity were determined. Our results showed that metformin reversed STZ-induced impairments in spatial learning/memory performance and sociability, coinciding with normalization of brain glucose transport, uptake and metabolism. Microgliosis and astrogliosis were ameliorated by metformin in sAD model rats. Metformin also preserved hippocampal synaptic plasticity and normalized acetylcholine cleavage in the cortical and hippocampal tissues, as well as inhibited acetylcholine esterase activity in vitro. These data indicate the promise of further research of metformin in early brain pathologies to stop neurodegenerative before severe cognitive decline occurs.

1762-P: Poor Sleep Quality Is Associated with Lower Absolute Cerebral Glucose Levels

Poor sleep quality has been associated with increased risk of metabolic syndrome and type 2 diabetes as well as acceleration of neurodegenerative diseases. In rodents, sleep restriction decreases glucose transport into the brain via downregulation of GLUT1, the primary glucose transporter at the blood-brain barrier. However, little is known about the association between sleep quality and glucose transport and metabolism in the human brain. In this exploratory analysis, we quantified cerebral glucose levels amongst individuals with good and poor sleep quality as defined by the widely used and well-validated Pittsburgh Sleep Quality Index (PSQI), which assesses 7 different components of sleep quality over a 1 month time period (PSQI≥5 = Poor sleep; PSQI&amp;lt;5 = Good sleep). Twelve healthy subjects completed the PSQI questionnaire. Eight (6F, age 27.6 ± 5.7, BMI 26.6 ± 8.2 kg/m2, HgbA1c 5.4 ± 0.2%) had good and 4 (2F, age 29.5± 2.4, BMI 27.8 ± 6.5 kg/m2, HgbA1c 5.2 ± 0.2%) had poor sleep. All subjects underwent 13C magnetic resonance spectroscopy brain scanning at 4 Tesla during a 2-hour hyperglycemic clamp (plasma glucose target ∼180 mg/dl) to measure absolute cerebral glucose levels as part of a larger study to investigate obesity and cerebral glucose metabolism. There were no differences in age, BMI, or HbA1c levels between groups with good and poor sleep. Individuals with good sleep had 63% higher absolute cerebral glucose levels at steady state compared to those with poor sleep (3.4 ± 0.7 mmol/L vs. 2.1 ± 0.9 mmol/L, p=.017). Higher PSQI scores correlated with lower absolute cerebral glucose levels (r= -0.725, p=0.008, PSQI for all subjects (mean±SD) = 4 ± 2). In this pilot and exploratory study, individuals with poor sleep quality have significantly lower absolute cerebral glucose levels, which suggests an association between poor sleep and altered cerebral glucose transport and/or metabolism. These findings may have wide-ranging implications for understanding the effects of sleep on brain function. Disclosure T.K. Stanley: None. F. Gunawan: None. N.S. Redeker: None. L. Jiang: None. A. Coppoli: None. D.L. Rothman: None. G.F. Mason: None. J. Hwang: Research Support; Self; General Electric. Funding American Diabetes Association (1-17-ICTS-013 to J.H.); National Institutes of Health (1R03DK121048)

1772-P: Reversibility of Altered Brain Glucose Kinetics in T2DM

Poor glycemic control is associated with central nervous system complications. We have previously shown that compared to healthy controls, individuals with uncontrolled T2DM have a blunted rise in brain glucose levels measured by 1H magnetic resonance spectroscopy (MRS). In this study, we investigate whether reduction in HbA1C improves intracerebral glucose levels. Six T2DM subjects with poor glycemic control were recruited (4F, age 46.0 ± 8.8 yrs, BMI 34.2 ± 4.1 kg/m2, HgbA1c 9.6 ± 1.1%) to participate in 1HMRS scanning at 4 Tesla during a hyperglycemic clamp (∼220 mg/dl) before and after a 12-week intervention to improve glycemic control through use of continuous glucose monitoring, intensification of diabetes regimen, and frequent visits with an endocrinologist and nutritionist. Following the intervention, HbA1c decreased by 2.1%±1.5 (P=0.02) with minimal BMI changes (P=0.10). Using a hierarchical linear regression model to compare glucose time courses during the clamp pre and post intervention, brain glucose levels were modestly and significantly higher during the clamp after the intervention (P=0.02) despite no differences in plasma glucose levels during the clamp (P=0.45). These findings suggest that brain glucose levels increase after improvement of glycemic control and provide evidence that reducing HbA1C may improve brain glucose transport and/or metabolism. Disclosure E. Sanchez Rangel: None. F. Gunawan: None. L. Jiang: None. M. Savoye: None. F. Dai: None. D.L. Rothman: None. G.F. Mason: None. J.J. Hwang: Research Support; Self; General Electric. Funding National Institutes of Health (DK109284)

Reversibility of Brain Glucose Transport and Metabolism in T2DM: an Intervention Study

Reversibility of Brain Glucose Transport and Metabolism in T2DM: an Intervention Study

Prenatal electronic cigarette exposure decreases brain glucose utilization and worsens outcome in offspring hypoxic-ischemic brain injury.

It has been shown that prenatal nicotine and tobacco smoke exposure can cause different neurobehavioral disorders in the offspring. We hypothesize that prenatal exposure to nicotine-containing electronic cigarette (e-Cig) vapor can predispose newborn to enhanced sensitivity to hypoxic-ischemic (HI) brain injury and impaired motor and cognitive functions. In this study, pregnant CD1 mice were exposed to e-Cig vapor (2.4% nicotine). Primary cortical neurons isolated from e-Cig exposed fetus were exposed to oxygen-glucose deprivation followed by reoxygenation (OGD/R) to mimic HI brain injury. Cell viability and glucose utilization were analyzed in these neurons. HI brain injury was induced in 8-9-day-old pups. Short-term brain injury was evaluated by triphenyltetrazolium chloride staining. Long-term motor and cognitive functions were evaluated by open field, novel object recognition, Morris water maze, and foot fault tests. Western blotting and immunofluorescence were done to characterize glucose transporters in offspring brain. We found that e-Cig exposed neurons demonstrated decreased cell viability and glucose utilization in OGD/R. Prenatally e-Cig exposed pups also had increased brain injury and edema 24hr after HI brain injury. Further, in utero e-Cig exposed offspring with HI brain injury displayed impaired memory, learning, and motor coordination at adolescence. Additionally, the expression of glucose transporters decreased in e-Cig exposed offspring brain after HI brain injury. These results indicate that reduced glucose utilization can contribute to prenatal e-Cig exposure induced worsened HI brain injury in offspring. This study is instrumental in elucidating the possible deleterious effects of e-Cig use in the general population.

Impact of curcumin treatment on diabetic albino rats.

The current study was aimed to study the effect of curcumin on the expression levels of brain glucose transporter 1 protein (GLUT1) and femoral muscle glucose transporter 4 protein (GLUT4), in addition to study its possible therapeutic role in ameliorating insulin resistance and the metabolic disturbance in the obese and type 2 diabetic male albino Wistar rat model. Diabetes was induced by a high-fat (HF) diet with low dose streptozotocin (STZ). Curcumin was administered intragastrically for 8 weeks (80 mg/kg BW/day). The HF-diet group developed obesity, hyperglycemia, hyperinsulinemia, reduced liver glycogen content with significant dyslipidemia. In the diabetic control group, hyperglycemia and insulin resistance high calculated homeostasis model assessment (HOMA-IR-index score) were pronounced, with reductions in liver and muscle glycogen contents, concomitant with dyslipidemia and significantly elevated malondialdehyde levels in liver and pancreas. GLUT1 and GLUT4 were down-regulated in the obese and the diabetic control groups, respectively. Curcumin, showed glucose-lowering effect and decreased insulin resistance, dyslipidemia and malondialdehyde levels in both tissues, it increased liver & muscle glycogen contents, compared to the diabetic control. Curcumin significantly up-regulated GLUT4 gene expression, compared to the diabetic control group. In conclusions, these results indicate a therapeutic role of curcumin in improving the diabetic status, obesity and enhancing the expression of GLUT4 gene.

SAT-248 Maternal Iron Deficiency Alters Brain Glucose, Lactate and Thyroxine Transport in Developing Neonatal Rats

Thyroid hormone insufficiency and iron deficiency (FeD) during fetal and neonatal life are both similarly deleterious to mammalian development suggesting a possible linkage between iron and thyroid hormone insufficiencies. Published data from our laboratory demonstrate a reduction in circulating and brain thyroid hormone levels in neonatal rats when dams are fed an iron deficient diet. We have also previously reported an observed increase in brain vascular density in iron deficient neonatal rats as a possible compensatory mechanism for increasing oxygen delivery to the developing brain. We now report the effects of gestational and neonatal FeD on glucose, lactate, and thyroxine transport in the neonatal rat brain. Gestational day 2 (G2) Sprague-Dawley rat dams were assigned to two groups. The Control group was fed a standard chow diet with 84 ppm iron while the FeD group was fed an iron deficient diet (10 ppm Fe). All animals were maintained on the defined diets from G2 through weaning. Serum hemoglobin, glucose, lactate and thyroxine levels were measured at postnatal days 7 (P7), 14, and 21. Blood vessel density was assessed by immunohistochemistry. Finally, a brain perfusion method was developed to quantify total brain vascular volume and measure transport rates for substrates glucose, lactate, and thyroxine. Hemoglobin levels were significantly reduced by 40% in FeD P7 up to 60% by P21 indicating a marked reduction in iron stores was achieved at all ages in the FeD group. Consistent with our previously reported findings, we found significant 23% reductions in serum T4 in FeD pups at P14 and 36% increases in cortical blood vessel density. Brain vascular volume was similarly significantly increased at P14 (31%) and P21 (37%). Importantly, we found that glucose, lactate, and thyroxine blood-to-brain transport rates were all increased in the FeD neonates. Glucose transport rates significantly increased by 57% at P14 and 90% by P21. Lactic acid transport rates were significantly elevated by 44% at P14 and 36% at P21. Thyroxine transport rates were significantly increased by 23% at P14 only. Assessment of neonatal hypoxic hypoxia treatment on brain glucose transport is currently in progress. Together our data demonstrate a significant impact of gestational and neonatal iron deficiency on nutrient and thyroid hormone transport in the developing brain. Increased vascular density and vascular volume may explain the magnitude of increased lactate and thyroxine transport. However, the more substantially increased glucose transport rate suggests additional mechanisms of glucose transport regulation are altered during iron deficiency. Alterations in nutrient and hormone transport homeostasis may contribute to the developmental brain pathology associated with neonatal iron deficiency.

Vernonia Amygdalina Del. stimulated glucose uptake in brain tissues enhances antioxidative activities; and modulates functional chemistry and dysregulated metabolic pathways.

Brain glucose uptake is usually reduced in type 2 diabetes owing to downregulation of brain glucose transporters. The ability of Vernonia amygdalina to stimulate glucose uptake as well as ameliorate glucose-induced oxidative stress and proinflammation were investigated in rat brain. Hot infusion of V. amygdalina leaves was incubated with rat brain tissues for 2h in the presence of glucose. Another incubation with glucose only, served as negative control while metformin served aspositive control. Incubation of brain tissues with V. amygdalina led to significant (p < 0.05) increase inglucose uptake, reduced glutathione, nitric oxide and non-thiol proteins levels, superoxide dismutase, catalase and ATPase activities, while concomitantly decrease inmyeloperoxidase activity and malondialdehyde level compared to the negativecontrol. Incubation with glucose only, led to the development of nitrate, amide II and amide I functional groups which were removed on incubation with the infusion. LC-MS analysis revealed depletion of oxidativestress-induced 2-keto-glutaramic acid and cysteinyl-tyrosine metabolites in brain tissues, with concomitant generation of S-formylglutathione and adenosine tetraphosphate by the infusion. Pathway analysis of the metabolites revealed an activation of pyruvate metabolism pathway in the negative control, with the infusion reducing the intensity fold. LC-MS analysis of the infusion revealed the presence of l-serine, l-cysteine, l-proline, nicotinic acid, cumidine, salicylic acid, isoquinoline, 3-methyl-, and γ-octalactone. Except for l-serine, l-cysteine and l-proline, the other compounds were predicted to be permeable across the blood brain barrier. These results indicate the brain glucose uptake stimulatory and neuroprotective effect of V. amygdalina.