• brain injury
• intracerebral hemorrhage
• mechanisms
• microglia
• utilization strategies

• Blood Glucose
• Glycemic Control
• Intensive Care Units
• Prognosis
• Traumatic Brain Injury

• Humans
• Brain Injuries, Traumatic/blood
• Brain Injuries, Traumatic/mortality
• Brain Injuries, Traumatic/complications
• Male
• Female
• Middle Aged
• Retrospective Studies
• Prognosis
• Blood Glucose/analysis
• Blood Glucose/metabolism
• Adult
• Aged
• Hospital Mortality
• Glasgow Coma Scale
• Intensive Care Units/statistics & numerical data
• Databases, Factual
• Hyperglycemia/blood
• Hyperglycemia/mortality

• glaucoma
• molecular neuroscience
• neurodegeneration

• Animals
• Humans
• Mice
• Aqueous Humor/metabolism
• Cataract/metabolism
• Cross-Sectional Studies
• Gas Chromatography-Mass Spectrometry
• Glaucoma, Open-Angle/metabolism
• Glutamic Acid/metabolism
• Homeostasis
• Intraocular Pressure
• Lactic Acid/metabolism
• Retina/metabolism

• 21K09675 Japan Society for the Promotion of Science

• 1,2-13C2 glucose
• Brain metabolism
• NMR
• microdialysis
• traumatic brain injury (human)

• Humans
• Glucose/metabolism
• Glutamine/metabolism
• Brain/metabolism
• Microdialysis
• Lactic Acid/metabolism
• Pyruvic Acid/metabolism
• Dietary Supplements

• G1002277 Medical Research Council
• G0600986 ID79068 Medical Research Council
• G1002277 ID98489 Medical Research Council
• G0600986 Medical Research Council
• NIHR200986 Department of Health
• Wellcome Trust
• II-C5-0715-20005 Department of Health
• 220257/Z/20/Z Wellcome Trust
• MC_UU_00028/4 Medical Research Council
• G0802251 Medical Research Council

• excitatory neurotoxicity
• glutamate homeostasis
• neuropharmacological research
• posttraumatic epilepsy
• preventive treatment
• traumatic brain injury

• Humans
• Epilepsy, Post-Traumatic/drug therapy
• Epilepsy, Post-Traumatic/etiology
• Epilepsy, Post-Traumatic/prevention & control
• Brain Injuries, Traumatic/complications
• Brain Injuries, Traumatic/drug therapy
• Cognitive Dysfunction/complications
• Glutamic Acid
• Homeostasis

• Minerals
• Nutrition
• Supplements
• Traumatic brain injury
• Vitamins

• R25 NS108939 NINDS NIH HHS

• RNA-Seq
• brain
• ischemic stroke
• neuroprotection
• peptide regulation
• peptides
• transcriptomic analysis

• 19-14-00268 Russian Science Foundation

• cerebral microdialysis
• lactate/pyruvate ratio
• mitochondrial dysfunction
• multi-modality monitoring
• traumatic brain injury

• Humans
• Microdialysis/methods
• Brain Injuries, Traumatic/metabolism
• Glucose/metabolism
• Energy Metabolism/physiology
• Pyruvic Acid/metabolism
• Pyruvic Acid/therapeutic use
• Brain

• G1002277 Medical Research Council
• G0802251 Medical Research Council
• G1002277 ID98489 Medical Research Council
• BRC-1215-20014 Department of Health

Metabolic dysfunction is a ubiquitous underlying feature of many neurological conditions including acute traumatic brain injuries and chronic neurodegenerative conditions. A central problem in neurological patients, in particular those with traumatic brain injuries, is an impairment in the utilization of glucose, which is the predominant metabolic substrate in a normally functioning brain. In such patients, alternative substrates including ketone bodies and lactate become important metabolic candidates for maintaining brain function. While the potential neuroprotective benefits of ketosis have been recognized for up to almost a century, the majority of work has focused on the use of ketogenic diets to induce such a state, which is inappropriate in cases of acute disease due to the prolonged periods of time (i.e., weeks to months) required for the effects of a ketogenic diet to be seen. The following review seeks to explore the neuroprotective effects of exogenous ketone and lactate preparations, which have more recently become commercially available and are able to induce a deep ketogenic response in a fraction of the time. The rapid response of exogenous preparations makes their use as a therapeutic adjunct more feasible from a clinical perspective in both acute and chronic neurological conditions. Potentially, their ability to globally moderate long-term, occult brain dysfunction may also be relevant in reducing lifetime risks of certain neurodegenerative conditions. In particular, this review explores the association between traumatic brain injury and contusion-related dementia, assessing metabolic parallels and highlighting the potential role of exogenous ketone and lactate therapies.

• Blood-brain barrier
• GLUT1
• MCT1
• Mfsd2a
• SLC transporter

• Animals
• Astrocytes/metabolism
• Blood-Brain Barrier/metabolism
• Brain/metabolism
• Brain Diseases/metabolism
• Humans
• Lactic Acid/metabolism
• Membrane Transport Proteins/metabolism

• NMRC/OFIRG/0066/20 Ministry of Health -Singapore
• MOE2018-T2-1-126 Ministry of Education- Singapore
• NUSMED-FOS Ageing grant National University of Singapore
• MOE-Tier-1 Ministry of education Singapore

Glucose is the essential and almost exclusive metabolic fuel for the brain. Ischemic stroke caused by a blockage in one or more cerebral arteries quickly leads to a lack of regional cerebral blood supply resulting in severe glucose deprivation with subsequent induction of cellular homeostasis disturbance and eventual neuronal death. To make up ischemia-mediated adenosine 5′-triphosphate depletion, glucose in the ischemic penumbra area rapidly enters anaerobic metabolism to produce glycolytic adenosine 5′-triphosphate for cell survival. It appears that an increase in glucose in the ischemic brain would exert favorable effects. This notion is supported by in vitro studies, but generally denied by most in vivo studies. Clinical studies to manage increased blood glucose levels after stroke also failed to show any benefits or even brought out harmful effects while elevated admission blood glucose concentrations frequently correlated with poor outcomes. Surprisingly, strict glycaemic control in clinical practice also failed to yield any beneficial outcome. These controversial results from glucose management studies during the past three decades remain a challenging question of whether glucose intervention is needed for ischemic stroke care. This review provides a brief overview of the roles of cerebral glucose under normal and ischemic conditions and the results of managing glucose levels in non-diabetic patients. Moreover, the relationship between blood glucose and cerebral glucose during the ischemia/reperfusion processes and the potential benefits of low glucose supplements for non-diabetic patients are discussed.

• blood glucose
• blood-brain barrier
• cerebral glucose
• glucose intervention
• glucose transporter
• glycosylation
• induced hyperglycemia
• ischemic penumbra
• ischemic stroke
• non-diabetic patients

• HbA1c
• diabetes
• glucose
• intracerebral hemorrhage
• mortality

• blood glucose level
• hypoglycemia
• measurement
• non-invasive
• optical device

Although diet interventions are mostly related to metabolic disorders, nowadays they are used in a wide variety of pathologies. From diabetes and obesity to cardiovascular diseases, to cancer or neurological disorders and stroke, nutritional recommendations are applied to almost all diseases. Among such disorders, metabolic disturbances and brain function and/or diseases have recently been shown to be linked. Indeed, numerous neurological functions are often associated with perturbations of whole-body energy homeostasis. In this regard, specific diets are used in various neurological conditions, such as epilepsy, stroke, or seizure recovery. In addition, Alzheimer’s disease and Autism Spectrum Disorders are also considered to be putatively improved by diet interventions. Glycemic index diets are a novel developed indicator expected to anticipate the changes in blood glucose induced by specific foods and how they can affect various physiological functions. Several results have provided indications of the efficiency of low-glycemic index diets in weight management and insulin sensitivity, but also cognitive function, epilepsy treatment, stroke, and neurodegenerative diseases. Overall, studies involving the glycemic index can provide new insights into the relationship between energy homeostasis regulation and brain function or related disorders. Therefore, in this review, we will summarize the main evidence on glycemic index involvement in brain mechanisms of energy homeostasis regulation.

• cognition
• glycemia
• ketone bodies
• metabolism
• neurodegeneration
• nutrition
• nutrition therapy

The goal of neurocritical care in patients with traumatic brain injury (TBI) is to prevent secondary brain damage. Pathophysiological mechanisms lead to loss of body mass, negative nitrogen balance, dysglycemia, and cerebral metabolic dysfunction. All of these complications have been shown to impact outcomes. Therapeutic options are available that prevent or mitigate their negative impact. Nutrition therapy, glucose control, and multimodality monitoring with cerebral microdialysis (CMD) can be applied as an integrated approach to optimize systemic immune and organ function as well as adequate substrate delivery to the brain. CMD allows real-time bedside monitoring of aspects of brain energy metabolism, by measuring specific metabolites in the extracellular fluid of brain tissue. Sequential monitoring of brain glucose and lactate/pyruvate ratio may reveal pathologic processes that lead to imbalances in supply and demand. Early recognition of these patterns may help individualize cerebral perfusion targets and systemic glucose control following TBI. In this direction, recent consensus statements have provided guidelines and recommendations for CMD applications in neurocritical care. In this review, we summarize data from clinical research on patients with severe TBI focused on a multimodal approach to evaluate aspects of nutrition therapy, such as timing and route; aspects of systemic glucose management, such as intensive vs. moderate control; and finally, aspects of cerebral metabolism. Research and clinical applications of CMD to better understand the interplay between substrate supply, glycemic variations, insulin therapy, and their effects on the brain metabolic profile were also reviewed. Novel mechanistic hypotheses in the interpretation of brain biomarkers were also discussed. Finally, we offer an integrated approach that includes nutritional and brain metabolic monitoring to manage severe TBI patients.

• brain glucose
• cerebral microdialysis
• glucose control
• neurointensive care
• nutrition therapy

This study investigated the effects of vitamins D and E on an insulin-resistant model and hypothesized that this treatment would reverse the effects of Alzheimer’s disease (AD) and improves insulin signalling. An insulin-resistant model was induced in SK-N-SH neuronal cells with a treatment of 250 nM insulin and re-challenged with 100 nM at two different incubation time (16 h and 24 h). The effects of vitamin D (10 and 20 ng/mL), vitamin E in the form of tocotrienol-rich fraction (TRF) (200 ng/mL) and the combination of vitamins D and E on insulin signalling markers (IR, PI3K, GLUT3, GLUT4, and p-AKT), glucose uptake and AD markers (GSK3β and TAU) were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The results demonstrated an improvement of the insulin signalling pathway upon treatment with vitamin D alone, with significant increases in IR, PI3K, GLUT3, GLUT4 expression levels, as well as AKT phosphorylation and glucose uptake, while GSK3β and TAU expression levels was decreased significantly. On the contrary, vitamin E alone, increased p-AKT, reduced the ROS as well as GSK3β and TAU but had no effect on the insulin signalling expression levels. The combination of vitamins D and E only showed significant increase in GLUT4, p-AKT, reduced ROS as well as GSK3β and TAU. Thus, the universal role of vitamin D, E alone and in combinations could be the potential nutritional agents in restoring the sensitivity of neuronal cells towards insulin and delaying the pathophysiological progression of AD.

• SK-N-SH neuronal cells
• glucose uptake
• insulin resistance
• vitamin D
• vitamin E

• Cell Line, Tumor
• Gene Expression Regulation/drug effects
• Humans
• Insulin Resistance
• Neuroblastoma
• Neurons/drug effects
• Phosphatidylinositol 3-Kinases/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins c-akt/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• Signal Transduction/drug effects
• Vitamin D/pharmacology
• Vitamin E/pharmacology

• Inflammation
• lactate pyruvate ratio (LPR)
• metabolic dysfunction
• metabolism
• supplementation
• traumatic brain injury (TBI)

• multimodal monitoring
• neuro intensive care
• traumatic brain injury
• treatment

Fourteen glucose transporters (GLUTs) play essential roles in human physiology by facilitating glucose diffusion across the cell membrane. Due to its central role in the energy metabolism of the central nervous system, GLUT3 has been thoroughly investigated. However, the Gibbs free-energy gradient (what drives the facilitated diffusion of glucose) has not been mapped out along the transport path. Some fundamental questions remain. Here we present a molecular dynamics study of GLUT3 embedded in a lipid bilayer to quantify the free-energy profile along the entire transport path of attracting a β-d-glucose from the interstitium to the inside of GLUT3 and, from there, releasing it to the cytoplasm by Arrhenius thermal activation. From the free-energy profile, we elucidate the unique Michaelis–Menten characteristics of GLUT3, low K_M and high V_MAX, specifically suitable for neurons’ high and constant demand of energy from their low-glucose environments. We compute GLUT3’s binding free energy for β-d-glucose to be −4.6 kcal/mol in agreement with the experimental value of −4.4 kcal/mol (K_M = 1.4 mM). We also compute the hydration energy of β-d-glucose, −18.0 kcal/mol vs the experimental data, −17.8 kcal/mol. In this, we establish a dynamics-based connection from GLUT3’s crystal structure to its cellular thermodynamics with quantitative accuracy. We predict equal Arrhenius barriers for glucose uptake and efflux through GLUT3 to be tested in future experiments.

• Glucose transporter
• binding affinity
• facilitated diffusion
• free energy
• molecular dynamics

• electrochemical sensors
• microdialysis
• microfabrication
• neural probes
• neurochemistry

• Animals
• Brain/metabolism
• Brain Chemistry
• Electrochemical Techniques/instrumentation
• Humans
• Microelectrodes
• Microtechnology/instrumentation

• R01 EB003320 NIBIB NIH HHS
• R37 EB003320 NIBIB NIH HHS

Optimal glycaemic targets for patients with severe traumatic brain injury remain unclear. The primary objective of this microdialysis study was to compare cerebral metabolism with strict versus conventional glycaemic control.

We performed a prospective single-centre randomised controlled within-subject crossover study of 20 adult patients admitted to an academic neurointensive care unit with severe traumatic brain injury. Patients underwent randomised, consecutive 24-h periods of strict (4–7 mmol/L; 72–126 mg/dl) and conventional (<10 mmol/L; 180 mg/dl) glycaemic control with microdialysis measurements performed hourly. The first 12 h of each study period was designated as a ‘washout’ period, with the subsequent 12 h being the period of interest.

Cerebral glucose was lower during strict glycaemia than with conventional control (mean 1.05 [95% CI 0.58–1.51] mmol/L versus 1.28 [0.81–1.74] mmol/L; P = 0.03), as was lactate (3.07 [2.44–3.70] versus 3.56 [2.81–4.30]; P < 0.001). There were no significant differences in pyruvate or the lactate/pyruvate ratio between treatment phases. Strict glycaemia increased the frequency of low cerebral glucose (< 0.8 mmol/L; OR 1.91 [95% CI 1.01–3.65]; P < 0.05); however, there were no differences in the frequency of critically low glucose (< 0.2 mmol/L) or critically elevated lactate/pyruvate ratio between phases.

Compared with conventional glycaemic targets, strict blood glucose control was associated with lower mean levels of cerebral glucose and an increased frequency of abnormally low glucose levels. These data support conventional glycaemic targets following traumatic brain injury.

ISRCTN, ISRCTN19146279. Retrospectively registered on 2 May 2014.

The online version of this article (10.1186/s13054-017-1933-5) contains supplementary material, which is available to authorized users.

• Glucose
• Insulin
• Microdialysis
• Traumatic brain injury

Metabolic abnormalities are commonly observed in traumatic brain injury (TBI) patients exhibiting long-term neurological deficits. This study investigated the feasibility and reproducibility of using chemical exchange saturation transfer (CEST) MRI to detect cerebral metabolic depression in experimental TBI. Phantom and in vivo CEST experiments were conducted at 9.4 Tesla to optimize the selective saturation for enhancing the endogenous contrast-weighting of the proton exchanges over the range of glucose proton chemical shifts (glucoCEST) in the resting rat brain. The optimized glucoCEST-weighted imaging was performed on a closed-head model of diffuse TBI in rats with 2-deoxy-D-[¹⁴C]-glucose (2DG) autoradiography validation. The results demonstrated that saturation duration of 1‒2 seconds at pulse powers 1.5‒2µT resulted in an improved contrast-to-noise ratio between the gray and white matter comparable to 2DG autoradiographs. The intrasubject (n = 4) and intersubject (n = 3) coefficient of variations for repeated glucoCEST acquisitions (n = 4) ranged between 8‒16%. Optimization for the TBI study revealed that glucoCEST-weighted images with 1.5μT power and 1 s saturation duration revealed the greatest changes in contrast before and after TBI, and positively correlated with 2DG autoradiograph (r = 0.78, p < 0.01, n = 6) observations. These results demonstrate that glucoCEST-weighted imaging may be useful in detecting metabolic abnormalities following TBI.

• Cerebral microdialysis
• Glucose control
• Hyperglycolysis
• Metabolic crisis
• Metabolism
• Neurovascular unit
• Outcome
• Traumatic brain injury

Diabetes is a metabolic health disorder and an important risk factor for stroke. Phosphoprotein enriched in astrocytes 15 (PEA-15) is a multifunctional protein modulating cell proliferation, survival, apoptosis and glucose metabolism. This study investigated whether diabetes modulates the expression of PEA-15 and two phosphorylated forms (Ser 104 and Ser 116) in middle cerebral artery occlusion (MCAO)-induced brain injury. Male Sprague-Dawley rats were administrated with streptozotocin (40 mg/kg) and were underwent right middle cerebral artery occlusion (MCAO) 4 weeks after streptozotocin injection. Brain tissues were collected 24 hr after MCAO and stained using triphenyltetrazolium chloride. Western blot analysis was performed to elucidate the expression of PEA-15 and two phosphorylated forms (Ser 104 and Ser 116) in right cerebral cortex. Infarct volume during MCAO injury was severely increased in diabetic animals compared to non-diabetic animals. We identified the decrease in PEA-15 in animals that underwent MCAO using proteomic approach. PEA-15 expression during MCAO was strongly decreased in diabetic animals compared to non-diabetic animals. Western blots analysis confirmed that diabetes exacerbated the decrease in PEA-15 expression after MCAO. Moreover, decrease in expression of phospho-PEA-15 (Ser 104 and Ser 116) was greater in diabetic than in non-diabetic animals. These results suggested that a diabetic condition may aggravate brain damage through decreasing expression of PEA-15 and phospho-PEA-15 (Ser 104 and Ser 116) in ischemic brain injury.

• Brain injuries
• Cerebrolysin
• Cerebrovascular trauma
• Cytidine diphosphate choline
• Piracetam
• Therapy

• inflammatory response
• nerve regeneration
• neural regeneration
• nuclear factor-kappa B
• tumor necrosis factor alpha

• electrocorticography
• multi-modal monitoring
• spreading depression

• Streptococcus suis; zoonotic infection; gastro-intestinal infection; food-borne pathogen; intestinal translocation

To analyze the mechanism of neuroprotection of insulin and which blood glucose range was benefit for insulin exerting neuroprotective action.

The study is based on the data from PubMed.

Articles were selected with the search terms “insulin”, “blood glucose”, “neuroprotection”, “brain”, “glycogen”, “cerebral ischemia”, “neuronal necrosis”, “glutamate”, “γ-aminobutyric acid”.

Insulin has neuroprotection. The mechanisms include the regulation of neurotransmitter, promoting glycogen synthesis, and inhibition of neuronal necrosis and apoptosis. Insulin could play its role in neuroprotection by avoiding hypoglycemia and hyperglycemia.

Intermittent and long-term infusion insulin may be a benefit for patients with ischemic brain damage at blood glucose 6–9 mmol/L.

• Adult
• Blood Glucose/analysis
• Brain Injuries/blood
• Brain Injuries/therapy
• Critical Care/methods
• Critical Illness/therapy
• Energy Intake/physiology
• Female
• Follow-Up Studies
• Humans
• Hyperglycemia/prevention & control
• Hypoglycemia/prevention & control
• Insulin/administration & dosage
• Insulin/therapeutic use
• Male
• Middle Aged
• Young Adult

• ¹³c labelling
• glucose
• magnetic resonance spectroscopy
• microdialysis
• positron emission tomography
• traumatic brain injury

• Animals
• Autoradiography/methods
• Brain Injuries/diagnosis
• Brain Injuries/metabolism
• Brain Injuries/physiopathology
• Energy Metabolism/physiology
• Extracellular Fluid/metabolism
• Glucose/metabolism
• Humans
• Magnetic Resonance Imaging/methods
• Microdialysis/methods
• Positron-Emission Tomography/methods

• G1002277 Medical Research Council
• G1000183 Medical Research Council
• G0802251 Medical Research Council
• G0001354 Medical Research Council
• NIHR-RP-R3-12-013 Department of Health
• G1002277 ID 98489 Medical Research Council

• acute brain injury (human)
• biomarkers
• blood–brain barrier
• cell death
• cerebral energy metabolism
• imaging
• inflammation
• multimodality monitoring

• Adolescent
• Adult
• Aged
• Blood Glucose/metabolism
• Blood Pressure/physiology
• Brain Injuries/metabolism
• Brain Injuries/physiopathology
• Cerebrovascular Circulation/physiology
• Female
• Humans
• Intracranial Pressure/physiology
• Male
• Middle Aged
• Retrospective Studies
• Young Adult

• G0001237 Medical Research Council
• G1002277 Medical Research Council
• G9439390 Medical Research Council
• G0600986 Medical Research Council
• G0001354 Medical Research Council
• NIHR-RP-R3-12-013 Department of Health

• Abstainers
• Abstinence
• Alcohol
• Alcohol users
• Fasting
• Glycemic allostasis
• Mental activities
• Sobriety

• astrocyte
• lactate
• microdialysis
• neuron
• pyruvate
• traumatic brain injury

• Adolescent
• Adult
• Alanine/administration & dosage
• Alanine/blood
• Alanine/metabolism
• Brain Injuries/diagnosis
• Brain Injuries/drug therapy
• Brain Injuries/metabolism
• Dipeptides/administration & dosage
• Dipeptides/blood
• Dipeptides/metabolism
• Female
• Glutamic Acid/blood
• Glutamic Acid/metabolism
• Glutamine/administration & dosage
• Glutamine/blood
• Glutamine/metabolism
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Severity of Illness Index
• Young Adult

• cerebral glucose metabolism
• hyperglycemia
• hypoglycemia
• insulin therapy
• stroke