Cerebral Glucose Levels Research Articles

Preliminary Observations of the Loke Microdialysis in an Experimental Pig Model: Are We Ready for Continuous Monitoring of Brain Energy Metabolism?

Brain energy metabolism is often disturbed after acute brain injuries. Current neuromonitoring methods with cerebral microdialysis (CMD) are based on intermittent measurements (1-4 times/h), but such a low frequency could miss transient but important events. The solution may be the recently developed Loke microdialysis (MD), which provides high-frequency data of glucose and lactate. Before clinical implementation, the reliability and stability of Loke remain to be determined in vivo. The purpose of this study was to validate Loke MD in relation to the standard intermittent CMD method. Four pigs aged 2-3 months were included. They received two adjacent CMD catheters, one for standard intermittent assessments and one for continuous (Loke MD) assessments of glucose and lactate. The standard CMD was measured every 15 min. Continuous Loke MD was sampled every 2-3 s and was averaged over corresponding 15-min intervals for the statistical comparisons with standard CMD. Intravenous glucose injections and intracranial hypertension by inflation of an intracranial epidural balloon were performed to induce variations in intracranial pressure, cerebral perfusion pressure, and systemic and cerebral glucose and lactate levels. In a linear mixed-effect model of standard CMD glucose(mM), there was a fixed effect value (± standard error [SE]) at 0.94 ± 0.07 (p < 0.001) for Loke MD glucose(mM), with an intercept at - 0.19 ± 0.15 (p = 0.20). The model showed a conditional R2 at 0.81 and a marginal R2 at 0.72. In a linear mixed-effect model of standard CMD lactate(mM), there was a fixed effect value (± SE) at 0.41 ± 0.16 (p = 0.01) for Loke MD lactate(mM), with an intercept at 0.33 ± 0.21 (p = 0.25). The model showed a conditional R2 at 0.47 and marginal R2 at 0.17. The established standard CMD glucose thresholds may be used as for Loke MD with some caution, but this should be avoided for lactate.

The Dual Role of Glutamatergic Neurotransmission in Alzheimer's Disease: From Pathophysiology to Pharmacotherapy.

Alzheimer’s disease (AD) is an age-related dementia and neurodegenerative disorder, characterized by Aβ and tau protein deposition impairing learning, memory and suppressing synaptic plasticity of neurons. Increasing evidence suggests that there is a link between the glucose and glutamate alterations with age that down-regulates glucose utilization reducing glutamate levels in AD patients. Deviations in brain energy metabolism reinforce the development of AD by hampering glutamate levels in the brain. Glutamate is a nonessential amino acid and the major excitatory neurotransmitter synthesized from glucose. Alterations in cerebral glucose and glutamate levels precede the deposition of Aβ plaques. In the brain, over 40% of neuronal synapses are glutamatergic and disturbances in glutamatergic function have been implicated in pathophysiology of AD. Nevertheless, targeting the glutamatergic system seems to be a promising strategy to develop novel, improved therapeutics for AD. Here, we review data supporting the involvement of the glutamatergic system in AD pathophysiology as well as the efficacy of glutamatergic agents in this neurodegenerative disorder. We also discuss exciting new prospects for the development of improved therapeutics for this devastating disorder.

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)

The acute effect of baobab fruit on cognitive performance, cerebral blood flow and blood glucose levels.

AbstractBaobab fruit contains high levels of phenolic compounds and vitamin C. Previous work has associated these phenolic compounds and vitamin C with a range of health benefits including improvements in cerebral blood flow and cognition. In vivo, it has been demonstrated that consumption of baobab fruit can reduce the glycaemic response, which may provide a mechanism for cognitive benefits as other research has shown that variations in blood glucose levels can modulate cognitive performance. Preliminary work found that consumption of 15 g baobab fruit extract significantly improved reaction time but increased number of errors on an executive function task. Taken together it would suggest baobab fruit has the potential to improve cognitive performance that could be attributed to changes in cerebral blood flow and blood glucose levels.The current study aimed to determine the effect of baobab fruit on cognitive performance, cerebral blood flow and blood glucose levels in a healthy young sample.This randomised, placebo-controlled, double-blind, counterbalanced-crossover study assessed the effect of 10 g baobab fruit powder or sugar matched control in 24 healthy participants (17 female, 7 male, mean age = 22.91 SD = 3.37). All participants completed the cognitive assessments, a subset of 14 completed the cerebral blood flow and blood glucose assessments (mean age = 23.21, SD = 2.46). Participants completed baseline tasks before consuming a drink containing either 10 g baobab fruit powder or placebo, there was then a 45-minute absorption period before participants completed cognitive tasks again. Seven days after participants returned and completed the same procedure but consumed the opposite drink. In the 14 participant subset, cerebral blood flow was measured throughout using Near Infrared Spectroscopy (NIRS) and blood glucose was measured before testing, after absorption period and upon completion of post doseUsing the MIXED procedure in SPSS, results showed that after consumption of baobab there was improved accuracy on a sustained attention task and fewer errors on the last repetition of a serial subtraction task. Baobab consumption led to increased blood glucose levels but there was no significant effect on cerebral blood flow.Results show that, in this sample, 10 g baobab fruit can improve certain aspects of cognitive performance and increase circulating blood glucose levels, which may explain these improvements. However, there was no significant effect on any cerebral blood flow measures. Future work may wish to explore further glucoregulation activity (in particular insulin response) after baobab consumption as a potential underlying mechanism.

Resveratrol Activates Neuronal Autophagy Through AMPK in the Ischemic Brain.

During cerebral ischemia, oxygen and glucose levels decrease, producing many consequences such as the generation of reactive oxygen species, tissue injury, and the general metabolism collapse. Resveratrol triggers signaling dependent on the protein kinase activated by adenosine monophosphate (AMPK), the sensor of cellular energy metabolism that regulates autophagy, eliminates damaged mitochondria, and increases energy sources. In the present study, we investigated the participation of AMPK activation in the protective effect of resveratrol on cerebral ischemia and excitotoxicity. We found that resveratrol increased the levels of phosphorylated AMPK in the cerebral cortex of rats subjected to middle cerebral artery occlusion (MCAO) and in primary cultured neurons exposed to glutamate-induced excitotoxicity. Resveratrol (1.8 mg/Kg; i. v.; administered at the beginning of reperfusion) decreased the infarct area and increased survival of rats subjected to MCAO. In neuronal cultures, resveratrol treatment (40 μM, after excitotoxicity) reduced the production of superoxide anion, prevented the overload of intracellular Ca+2 associated to mitochondrial failure, reduced the release of the lactate dehydrogenase enzyme, and reduced death. It also promoted mitophagy (increased Beclin 1 level, favored the recruitment of LC3-II, reduced LAMP1, and reduced mitochondrial matrix protein HSP60 levels). In both models, inhibition of AMPK activation with Compound C obstructed the effect of resveratrol, showing that its protective effect depends, partially, on the activation of the AMPK/autophagy pathway.

Research in brief: The effect of baobab fruit on cognitive function, cerebral blood flow and blood glucose levels

The baobab tree is native to Africa and locally has a wide range of culinary and medicinal uses. The fruit of the tree is high in nutrients, particularly vitamin C and polyphenols. This article summarises a preliminary study in which it was demonstrated 10g baobab fruit powder could improve a range of cognitive performance outcomes (in particular error responses and accuracy), increase cerebral blood flow and increase blood glucose levels in a healthy young sample.

Enteral nutrition increases interstitial brain glucose levels in poor-grade subarachnoid hemorrhage patients

Low brain tissue glucose levels after acute brain injury are associated with poor outcome. Whether enteral nutrition (EN) reliably increases cerebral glucose levels remains unclear. In this retrospective analysis of prospectively collected observational data, we investigate the effect of EN on brain metabolism in 17 poor-grade subarachnoid hemorrhage (SAH) patients undergoing cerebral microdialysis (CMD) monitoring. CMD-values were obtained hourly. A nutritional intervention was defined as the clinical routine administration of EN without supplemental parenteral nutrition. Sixty-three interventions were analyzed. The mean amount of EN per intervention was 472.4 ± 10.7 kcal. CMD-glucose levels significantly increased from 1.59 ± 0.13 mmol/l at baseline to a maximum of 2.03 ± 0.2 mmol/l after 5 h (p < 0.001), independently of insulin-treatment, baseline serum glucose, baseline brain metabolic distress (CMD-lactate-to-pyruvate-ratio (LPR) > 40) and the microdialysis probe location. The increase in CMD-glucose was directly dependent on the magnitude of increase of serum glucose levels (p = 0.007). No change in CMD-lactate, CMD-pyruvate, CMD-LPR, or CMD-glutamate (p > 0.4) was observed. Routine EN also increased CMD-glucose even if baseline concentrations were critically low ( < 0.7 mmol/l, neuroglucopenia; p < 0.001). These results may have treatment implications regarding glucose management of poor-grade aneurysmal SAH patients.

Does glycemic level affect neurologic outcomes during cardiopulmonary bypass?

Perioperative hyperglycaemia, aggravated by cardiopulmonary bypass (CPB), is associated with adverse outcomes. Increased potential for stroke in these patients may be improved by different interventions. Blood glucose level changes as an intrinsic response to both stress and extrinsic sources; might affect early mortality and morbidity. In this study, we tried to identify a relationship existence between cerebral arterial oxygen saturation (rSO2) and blood glucose levels, and thus; evaluate changes in rSO2 caused by changes in blood glucose levels measured at predetermined time points of CPB. Forty six patients with American Society of Anaesthesiologists (ASA) physical status at least III and even IV, undergoing elective open cardiac surgery were prospectively studied. Preparation for surgery, anaesthesia and perioperative vital data monitoring (five-channel) ECG, pulse oximetry, capnography, nasopharynx and rectal temperature, invasive arterial blood pressure, central venous pressure and near-infrared spectroscopy (NIRS) monitoring were done in the same standardised way for each patient. The Mini-Mental State Examination (MMT) questionnaire was used for these patients before and 24 hours after the operation to assess neurologic adverse effects. NIRS values and blood glucose levels were sampled at the following stages of the intervention: the reference level (T0) was obtained immediately after cannulation of the arterial system and before anaesthesia; the second sample (T1) was taken 20 min after anaesthesia was introduced; the third sample (T3) was taken after 20 min of the aortic cross-clamp; the fourth sample (T4) was taken 20 min after the removal of the aortic cross-clamp; and the final sample (T5) was obtained 24 h after the surgery. No statistically signifi;cant relationship was found between changes in rSO2 and changes in blood glucose levels before surgery, after anaesthesia, ischemia, reperfusion, and surgery, in either diabetic or non-diabetic patients. Our findings showed increase in blood glucose levels and decrease in rSO2 as expected in ischemia and reperfusion periods of bypass. There was no significant difference between preoperative and postoperative MMT values of diabetic and non-diabetic patients. Cerebral oxygen saturation measured by NIRS may be a useful monitorization in open cardiac surgery. Our fndings suggests that hyper/hypoglycemia during surgery did not reflect changes in cerebral oxygenation, thus neurologic outcomes when other variables remained constant. Further studies using this approach in different surgeries and patient groups are needed.

Adjuvant therapies using normobaric oxygen with hypothermia or ethanol for reducing hyperglycolysis in thromboembolic cerebral ischemia

Background and purpose: Normobaric oxygen (NBO), ethanol (EtOH), and therapeutic hypothermia (TH) delivered alone or in combination have neuroprotective properties after acute stroke. We used an autologous thromboembolic rat stroke model to assess the additive effects of these treatments for reducing the deleterious effects of hyperglycolysis post-stroke in which reperfusion is induced with recombinant tissue plasminogen activator (rt-PA).Methods: Sprague–Dawley rats were subjected to middle cerebral artery (MCA) occlusion with an autologous embolus. One hour after occlusion, rt-PA was administered alone or with NBO (60%), EtOH (1.0g/kg), TH (33°C), either singly or in combination. Infarct volume and neurological deficit were assessed at 24h after rt-PA-induced reperfusion with or without other treatments. The extent of hyperglycolysis, as determined by cerebral glucose and lactate levels was evaluated at 3 and 24h after rt-PA administration. At the same time points, expressions of glucose transporter 1 (Glut1), glucose transporter 3 (Glut3), phosphofructokinase1 (PFK-1), and lactate dehydrogenase were (LDH) measured by Western blotting.Results: Following rt-PA in rats with thromboembolic stroke, NBO combined with TH or EtOH most effectively decreased infarct volume and neurological deficit. As compared to rt-PA alone, EtOH or TH but not NBO monotherapies significantly reduced post-stroke hyperglycolysis. The increased utilization of glucose and production of lactate post-stroke was prevented most effectively when NBO was combined with either EtOH or TH after reperfusion with rt-PA, as shown by the significantly decreased Glut1, Glut3, PFK-1, and LDH levels.Conclusions: In a rat thromboembolic stroke model, both EtOH and TH used individually offer neuroprotection after the administration of rt-PA. While NBO monotherapy does not appear to be effective, it significantly potentiates the efficacy of EtOH and TH. The similar neuroprotection and underlying mechanisms pertaining to the attenuation of hyperglycolysis provided by EtOH or TH in combination with NBO suggest a possibility of substituting EtOH for TH. Thus a combination of NBO and EtOH, which are widely available and easily used, could become a novel and effective neuroprotective strategy in the clinical setting.

Effects of cerebral glucose levels in infarct areas on stroke injury mediated by blood glucose changes

Admission hyperglycemia is considered to be related to poor outcomes of ischemic stroke. However, there is controversy regarding effects of attempts to lower blood glucose in stroke patients. This study aimed at determining the effects of blood glucose fluctuation on stroke injury by detection of cerebral glucose levels. A single intraperitoneal injection of glucose (0, 0.5, 1, 1.5 or 2 g kg−1) at 5 min before reperfusion caused blood glucose fluctuation (5–15 mmol L−1) lasting for 2 h after reperfusion. Blood glucose levels of 6–10 mmol L−1 decreased stroke injury after reperfusion for 24 h and 28 days compared with conditions of hyperglycemia (>10 mmol L−1) and hypoglycemia (<6 mmol L−1). High glucose concentration increased neuronal injury and death after oxygen–glucose deprivation. Under hyperglycemia and hypoglycemia, elevations in expression of MMP-2/-9 and decrease of tight junction proteins including occludin, claudin-5 and ZO-1 contributed to blood–brain barrier (BBB) dysfunction in infarct regions after ischemia–reperfusion injury, and reduction of hexokinase, pyruvate kinase and lactate dehydrogenase activities significantly inhibited the glucose metabolism in cortex and striatum after 24 h of reperfusion. BBB damage and reduced glucose metabolism caused accumulation of glucose in infarct areas. An obvious increase in cerebral glucose levels aggravated stroke injury.

Patients with type 2 diabetes exhibit cognitive impairment with changes of metabolite concentration in the left hippocampus.

Type 2 diabetes mellitus (T2DM) is associated with cognitive dysfunction. Previous studies have reported the relationship between cerebral metabolite changes and glucose levels. However, the specific aspects of cognition that are affected by metabolic changes in T2DM- related cognitive impairment remain undetermined. In this study, 188 T2DM patients and 266 controls were recruited. Proton magnetic resonance spectra with a single voxel stimulated echo acquisition mode (STEAM) were acquired from the left hippocampus and the frontal lobe. Presence of T2DM negatively affected the scores of Mini-Mental State Examination (MMSE), sub-tests (i.e., attention and language) of MMSE, Montreal Cognitive Assessment (MoCA) according to the Beijing version, and sub-tests (i.e., visuospatial/executive reasoning, attention, and language) of MoCA, rather than the Wechsler Memory Scale – Revised in China (WMS-RC), and all memory sub-tests contained with the MMSE and MoCA frameworks. T2DM positively affected creatine and myoinositol peak areas from the left hippocampus, rather than metabolites in the left frontal lobe. Negative correlations were shown between the left hippocampal myoinositol levels and language scores, and between the left hippocampal creatine levels and visuospatial/executive scores in T2DM. These findings suggest that T2DM may be an independent risk factor for cognitive impairment. Further, the cognitive domains of visuospatial /executive reasoning, attention and language may be predominantly impaired in the early phases of T2DM-related cognitive impairment. In addition, left hippocampal myoinositol and creatine concentrations were associated with cognitive impairment in patients with T2DM.

Imaging liver and brain glycogen metabolism at the nanometer scale

In mammals, glycogen synthesis and degradation are dynamic processes regulating blood and cerebral glucose-levels within a well-defined physiological range. Despite the essential role of glycogen in hepatic and cerebral metabolism, its spatiotemporal distribution at the molecular and cellular level is unclear. By correlating electron microscopy and ultra-high resolution ion microprobe (NanoSIMS) imaging of tissue from fasted mice injected with 13C-labeled glucose, we demonstrate that liver glycogenesis initiates in the hepatocyte perinuclear region before spreading toward the cell membrane. In the mouse brain, we observe that 13C is inhomogeneously incorporated into astrocytic glycogen at a rate ~25 times slower than in the liver, in agreement with prior bulk studies. This experiment, using temporally resolved, nanometer-scale imaging of glycogen synthesis and degradation, provides greater insight into glucose metabolism in mammalian organs and shows how this technique can be used to explore biochemical pathways in healthy and diseased states. From the Clinical EditorBy correlating electron microscopy and ultra-high resolution ion microprobe imaging of tissue from fasting mice injected with 13C-labeled glucose, the authors demonstrate a method to image glycogen metabolism at the nanometer scale.

Resveratrol decreases inflammation in the brain of mice with mild traumatic brain injury

Following a mild traumatic brain injury (TBI) event, the secondary brain injury that persists after the initial blow to the head consists of excitotoxicity, decreased cerebral glucose levels, oxidant injury, mitochondrial dysfunction, inflammation, and neuronal cell death. To date, there are no effective interventions used at decreasing secondary brain injury after mild TBI. In this study, male mice were treated with either placebo or resveratrol (100 mg/kg) at 5 minutes and 12 hours after mild TBI. The mice were injured using the controlled cortical impact device. In this closed-head model, a midline incision was made to access the skull and the impactor tip was aligned on the sagittal suture midway between the bregma and lambda sutures. The mice were injured at a depth of 2.0 mm, velocity of 4 m/s, and a delay time of 100 milliseconds. At 72 hours following injury, the animals were intracardially perfused with 0.9% saline followed by 10% phosphate-buffered formalin. The whole brain was removed, sliced, and stained for microglial activation (Iba1). In addition, using the enzyme-linked immunosorbent assay, tissue levels of interleukin 6 (IL-6) and IL-12 were measured in the cerebral cortex and hippocampus. In this study, we found that in the placebo treatment group, there was a significant increase in Iba1 staining in the brain. The levels of microglial activation was reduced by resveratrol in the cerebral cortex (p < 0.001), corpus callosum (p < 0.001), and dentate gyrus (p < 0.005) brain regions after mild TBI. In addition to Iba1, resveratrol decreased the brain levels of IL-6 (p < 0.0001) and IL-12 (p < 0.004), which were observed in the hippocampus of the placebo group. In our model, no increase of IL-6 or IL-12 was observed in the cerebral cortex following TBI. Resveratrol given acutely after TBI results in a decrease in neuroinflammation. These results suggest that resveratrol may be beneficial in reducing secondary brain injury after experiencing a mild TBI.

Effects of insulin and amyloid β1–42 oligomers on glucose incorporation and mitochondrial function in cultured rat hippocampal neurons

The molecular basis for impaired glucose metabolism in patients with Alzheimer's disease (AD) has not been fully clarified. We tested whether insulin and amyloid (A)β(1-42) oligomers would regulate glucose metabolism and energy homeostasis directly in cultured rat hippocampal neurons and evaluated possible interactions between insulin signaling and Aβ(1-42) oligomers. Dissociated hippocampal neurons were prepared from Wistar rat embryos at day 21 of gestation and cultured for 14days. Cultured neurons were exposed to insulin (1µM) for 30min, and Aβ(1-42) oligomers (1µM) were added to culture media for 10-30min. The glucose uptake of cultured neurons was measured by enzymatic fluorescence assay using 2-deoxy-d-glucose (2DG), and adenosine triphosphate (ATP) contents were quantified using a luciferin/luciferase luminescence assay. Aβ(1-42) oligomers did not suppress 2DG uptake, reflecting the activities of glucose transporters and/or hexokinase, but led to disrupted ATP contents in the presence and absence of monocarboxylates (lactate/pyruvate). Insulin and C-peptide did not change glucose uptake or ATP concentrations. The primary target of Aβ(1-42) oligomers might be mitochondria, which could explain the reduced cerebral glucose levels in patients with AD. Moreover, insulin signaling was not directly linked to glucose metabolism or energy homeostasis in cultured rat hippocampal neurons.

Insulin differentially influences brain glucose and lactate in traumatic brain injured patients

Hypo- and hyperglycemia must be avoided to prevent additional brain damage following traumatic brain injury (TBI). However, the optimal blood glucose range requiring insulin remains unknown. Cerebral microdialysis is helpful in unmasking signs of metabolic impairment, thereby identifying deleterious blood glucose levels. A retrospective analysis of prospectively collected cerebral microdialysis samples obtained from 20 non-diabetic patients with severe TBI treated at the trauma surgical intensive care unit at the University Hospital Zürich, Switzerland. The impact of different arterial blood glucose values and concomitant insulin administration on cerebral interstitial glucose and lactate levels was investigated. In addition, energetic impairment was determined by calculating lactate-to-glucose ratios. Insulin administration was associated with significantly reduced cerebral glucose concentrations and significantly increased lactate-to-glucose ratios with arterial blood glucose levels <5 mM. At arterial blood glucose levels >7 mM, insulin administration was associated with significantly increased interstitial glucose values, significantly decreased lactate concentrations, and markedly diminished lactate-to-glucose ratios. Insulin exerts differential effects that depend strongly on the underlying arterial blood glucose concentrations. To avoid energetic impairment, insulin should not be administered at arterial blood glucose levels <5 mM. However, at arterial blood glucose levels >7-8 mM, insulin administration appears to be encouraged to increase extracellular glucose concentrations and decrease energetic impairment reflected by reduced interstitial brain lactate and decreased lactate-to-glucose ratios. Nevertheless, frequent analysis is required to minimize the risk of inducing impaired brain metabolism.

Is continuous insulin treatment safe in aneurysmal subarachnoid hemorrhage?

To investigate the long-term effect of continuous insulin infusion for glucose control on cerebral metabolism in aneurysmal subarachnoid hemorrhage (SAH) patients. Prospective, nonrandomized study of 31 SAH patients in the ICU (52 +/- 10 years, WFNS Grade 2.9 +/- 1.6). A microdialysis catheter was inserted into the vascular territory of the aneurysm. Metabolic changes during 4 days after onset of insulin infusion were analyzed. Blood glucose levels >140 mg/dL after clinical stabilization were treated with intravenous insulin. 24 patients were treated with intravenous insulin. Though no insulin-induced hypoglycemia occurred, cerebral glucose decreased on days 1-4 after insulin onset without reaching critical levels. Glycerol, a marker of membrane degradation, showed a reversible increase on day 1 while the lactate/pyruvate ratio remained stable and glutamate even decreased indicating absence of severe cerebral crisis following insulin infusion and excluding ischemia as a cause for cerebral glucose depletion. Concerning cerebral metabolism, long-term continuous insulin infusion appears to be safe as long as cerebral glucose levels do not fall below the physiological range. In view of the high incidence of hyperglycemia and need for insulin treatment, future studies on the effect of insulin on cerebral metabolism in SAH patients are desirable.

Insulin-related decrease in cerebral glucose despite normoglycemia in aneurysmal subarachnoid hemorrhage

IntroductionHyperglycaemia following aneurysmal subarachnoid hemorrhage (SAH) is associated with complications and impaired neurological recovery. The aim of this study was to determine the effect of insulin treatment for glucose control on cerebral metabolism in SAH patients.MethodsThis prospective, nonrandomized study was conducted in 31 SAH patients in an intensive care unit (age 52 ± 10 years, World Federation of Neurological Surgeons grade 2.9 ± 1.6). A microdialysis catheter was inserted into the vascular territory of the aneurysm after clipping. Blood glucose levels above 140 mg/dl were treated with intravenous insulin and the microdialysates were analyzed hourly for the first 12 hours of infusion.ResultsNo hypoglycaemia occurred. Twenty-four patients were treated with insulin for glucose control. Higher age and World Federation of Neurological Surgeons score were risk factors for need for insulin treatment (P < 0.05). Although blood glucose remained stable after initiation of insulin infusion, insulin induced a significant decrease in cerebral glucose at 3 hours after onset of the infusion until the end of the observation period (P < 0.05), reflecting high glucose utilization. The lactate:pyruvate ratio and glutamate did not increase, excluding ischaemia as possible cause of the decrease in glucose. Glycerol tended toward higher values at the end of the observation period (9 to 12 hours), reflecting either tissue damage after SAH or the beginning of cellular distress after insulin infusion.ConclusionHigher SAH grade was among the risk factors for need for insulin. Intensive glycaemic control using insulin induced a decrease of cerebral glucose and a slight increase in glycerol, though blood glucose remained normal. Future studies might detect relevant metabolic derangements when insulin treatment starts at low cerebral glucose levels, and may allow us to design a strategy for avoidance of insulin-induced metabolic crisis in SAH patients.

Insulin, intracerebral glucose and bedside biochemical monitoring utilizing microdialysis

Following subarachnoid hemorrhage, hyperglycemia is strongly associated with complications and with impaired neurological recovery. Targeted insulin therapy for glycemic control might, on the contrary, have harmful effects by causing too low cerebral glucose levels. The study published by Schlenk and colleagues in the previous issue of Critical Care shows that insulin caused a significant decrease in the interstitial cerebral glucose concentration although the blood glucose level remained unaffected. Since several studies utilizing various analytical techniques have shown that cerebral blood flow and cerebral glucose uptake and metabolism are insulin-independent processes, the observation remains unexplained.

Therapy Insight: the impact of type 1 diabetes on brain development and function

The CNS is one of the main organ systems that is affected in type 1 diabetes, as both cerebral glucose and insulin levels are frequently abnormal, even when the diabetes is well-controlled. Literature is emerging that documents pathophysiological CNS changes and neurocognitive deficits in both adults and children with type 1 diabetes, but empirical findings to date have often been inconsistent and difficult to interpret. This article provides a comprehensive review of current knowledge about the impact of type 1 diabetes on brain development and function, focusing particularly on the evidence for specific illness-related risk factors for CNS sequelae. We argue that clinical management of young patients with type 1 diabetes should take into account current knowledge of the relative risks of hypoglycemia and hyperglycemia to the developing brain.

The Primary Function of Rem Sleep

In this paper, the physiological features associated with the different stages of REM sleep and with what information processing researchers have called “effort” and “arousal” are compared. It is suggested that tonic REM sleep and effort involve an increase in the metabolism of cerebral glycogen, and phasic REM sleep and arousal involve the transfer of glucose from the body to the brain. Both stages of REM sleep seem to elevate cerebral glucose levels and likely result in increased ATP generation in some part(s) of the brain. It is noted that the functioning of the hippocampus depends heavily on ATP, and that this part of the brain becomes especially active during REM sleep. From this, although many details remain to be clarified, it seems clear that the primary function of REM sleep is to re-energize the brain.