The neurometabolic profiles of GABA and Glutamate as revealed by proton magnetic resonance spectroscopy in type 1 and type 2 diabetes (original) (raw)
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Diabetologia, 2019
Aims/hypothesis Chronic hyperglycaemia in type 1 diabetes affects the structure and functioning of the brain, but the impact of recurrent hypoglycaemia is unclear. Changes in the neurochemical profile have been linked to loss of neuronal function. We therefore aimed to investigate the impact of type 1 diabetes and burden of hypoglycaemia on brain metabolite levels, in which we assumed the burden to be high in individuals with impaired awareness of hypoglycaemia (IAH) and low in those with normal awareness of hypoglycaemia (NAH). Methods We investigated 13 non-diabetic control participants, 18 individuals with type 1 diabetes and NAH and 13 individuals with type 1 diabetes and IAH. Brain metabolite levels were determined by analysing previously obtained 1 H magnetic resonance spectroscopy data, measured under hyperinsulinaemic-euglycaemic conditions. Results Brain glutamate levels were higher in participants with diabetes, both with NAH (+15%, p = 0.013) and with IAH (+19%, p = 0.003), compared with control participants. Cerebral glutamate levels correlated with HbA 1c levels (r = 0.40; p = 0.03) and correlated inversely (r = −0.36; p = 0.04) with the age at diagnosis of diabetes. Other metabolite levels did not differ between groups, apart from an increase in aspartate in IAH. Conclusions/interpretation In conclusion, brain glutamate levels are elevated in people with type 1 diabetes and correlate with glycaemic control and age of disease diagnosis, but not with burden of hypoglycaemia as reflected by IAH. This suggests a potential role for glutamate as an early marker of hyperglycaemia-induced cerebral complications of type 1 diabetes. ClinicalTrials.gov NCT03286816; NCT02146404; NCT02308293 Keywords 1 H MRS. Brain. Euglycaemia. Glutamate. Type 1 diabetes Abbreviations CRLB Cramér-Rao lower bound CSF Cerebrospinal fluid IAH Impaired awareness of hypoglycaemia MAS Malate-aspartate shuttle MRS Magnetic resonance spectroscopy NAA N-acetylaspartate NAAG N-acetylaspartylglutamate NAH Normal awareness of hypoglycaemia SNR Signal-to-noise ratio TCA Tricarboxylic acid TE Echo time TR Repetition time
Neurochemical profile of patients with type 1 diabetes measured by ¹H-MRS at 4 T
Journal of Cerebral Blood Flow and Metabolism, 2013
The impact of type 1 diabetes mellitus (T1DM) on a comprehensive neurochemical profile of the human brain has not been reported yet. Our previous proton magnetic resonance spectroscopy (1 H-MRS) studies on T1DM were focused exclusively on the assessment of brain glucose levels. In this study, we reexamined our previously acquired data to investigate concentration differences of a broad range of neurochemicals in T1DM subjects relative to nondiabetic controls. We selected MRS data from 13 subjects (4 F/9 M, age ¼ 41 ± 11 years, body mass index ¼ 26 ± 3 kg/m 2) with well-controlled T1DM (disease duration ¼ 22 ± 12 years, A1C ¼ 7.5% ± 2.0%) and 32 nondiabetic controls (14 F/18 M, age ¼ 36 ± 10 years, body mass index ¼ 27 ± 6 kg/m 2) acquired during a hyperglycemic clamp (target [Glc] plasma ¼ 300±15 mg/dL). The 1 H-MR spectra were collected from two 15.6-mL voxels localized in gray-matter-rich occipital lobe and in white-matter-rich parieto-occipital region using ultra-short echo-time STEAM at 4 T. LCModel analysis allowed reliable quantification of 17 brain metabolites. Lower levels of N-acetylaspartate (by 6%, P ¼ 0.007) and glutamate (by 6%, P ¼ 0.045) were observed in the gray matter of T1DM patients as compared with controls, which might indicate a partial neuronal loss or dysfunction as a consequence of long-term T1DM. No other differences in metabolites were observed between subjects with T1DM and controls.
Cerebral glutamate metabolism during hypoglycaemia in healthy and type 1 diabetic humans
European Journal of Clinical Investigation, 2006
Background The mechanisms responsible for the progressive failure of hypoglycaemia counterregulation in long‐standing type 1 diabetes are poorly understood. Increased brain glucose uptake during hypoglycaemia or alterations of brain energy metabolism could effect glucose sensing by the brain and thus contribute to hypoglycaemia‐associated autonomic failure.Materials and methods Type 1 diabetic patients (T1DM) and healthy volunteers (CON) were studied before, during and after a hypoglycaemic (50 mg dL−1) hyperinsulinaemic (1·5 mU kg−1 min−1) clamp test. The 1H magnetic resonance spectroscopy of the occipital lobe of the brain was performed employing the STEAM localization technique. The water signal was suppressed by the modified SWAMP method. All spectra were acquired on a 3 Tesla scanner (80 cm MEDSPEC‐DBX, Bruker Medical, Ettlingen, Germany) using a 10‐cm diameter surface coil.Results During hypoglycaemia, T1DM showed blunted endocrine counterregulation. At baseline the brain t...
Journal of Diabetes and its Complications, 2008
The aim of this study was to investigate possible metabolic alterations in cerebral tissues on magnetic resonance spectroscopy (MRS) in patients with impaired glucose tolerance (IGT) and with type 2 diabetes mellitus (T2-DM). Twenty-five patients with T2-DM, 13 patients with IGT, and 14 healthy volunteers were included. Single-voxel spectroscopy (TR: 2000 ms, TE: 31 ms) was performed in all subjects. Voxels were placed in the frontal cortex, thalamus, and parietal white matter. N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, and myo-inositol (MI)/Cr ratios were calculated. Frontal cortical Cho/Cr ratios were increased in patients with IGT compared to control subjects. Parietal white matter Cho/Cr ratios were significantly higher in patients with IGT when compared to patients with T2-DM. In the diabetic group, frontal cortical MI/Cr ratios were increased, and parietal white matter Cho/Cr ratios were decreased when compared to the control group. Frontal cortical NAA/Cr and Cho/Cr ratios and parietal white matter Cho/Cr ratios were decreased in diabetic patients with poor glycemic control (A1CN10%). A1C levels were inversely correlated with frontal cortical NAA/Cr and Cho/Cr ratios and with parietal white matter Cho/Cr ratios. T2-DM and IGT may cause subtle cerebral metabolic changes, and these changes may be shown with MRS. Increased Cho/Cr ratios may suggest dynamic change in membrane turnover in patients with IGT. Diabetic patients with poor glycemic control may be associated with neuronal dysfunction/damage in brain in accordance with A1C levels and, in some, extend with insulin resistance. D
Abstract Cerebral metabolism will be affected in T2DM either by chronic hyperglycemia or by chronic hypoxia. Proton magnetic resonance spectroscopy (1H-MRS) of the brain provides detailed information about the structure, dynamics, reaction state and chemical environment of molecules. It also measures the levels of brain metabolites such as myo-inositol (mI), N acetyl aspartate (NAA), creatine (Cr), choline (Cho), glutamate (Glu), glutamine (Gln) and gamma amino butyric acid (GABA). Several studies suggest that people with type 2 diabetes mellitus (T2DM) are at an increased risk of cognitive impairment in comparison with the general population. The altered metabolites may cause cognitive dysfunction in T2DM. This review article concludes that in T2DM, metabolite levels were altered in different regions of brain.
Journal of Magnetic Resonance Imaging, 2018
Background: Type-2 diabetes mellitus (T2DM) is a metabolic disorder with a broad range of complications in the brain that depend on the conditions that precede its onset, such as obesity and metabolic syndromes. It has been suggested that neurotransmitter and metabolic perturbations may emerge even before the early stages of T2DM and that highcaloric intake could adversely influence the brain in such states. Notwithstanding, evidence for neurochemical and structural alterations in these conditions are still sparse and controversial. Purpose: To evaluate the influence of high-fat diet in the neurochemical profile and structural integrity of the rodent brain. Study Type: Prospective. Subjects: Wistar rats (n 5 12/group). Field Strength/Sequence: A PRESS, ISIS, RARE, and EPI sequences were performed at 9.4T. Assessment: Neurochemical and structural parameters were assessed by magnetic resonance spectroscopy, voxelbased morphometry, volumetry, and diffusion tensor imaging. Statistical Tests: Measurements were compared through Student and Mann-Whitney tests. Pearson correlation was used to assess relationships between parameters. Results: Animals submitted to high-caloric intake gained weight (P 5 0.003) and developed glucose intolerance (P < 0.001) but not hyperglycemia. In the hippocampus, the diet induced perturbations in glutamatergic metabolites reflected by increased levels of glutamine (P 5 0.016) and glutamatergic pool (Glx) (P 5 0.036), which were negatively correlated with glucose intolerance (glutamine, r 5-0.804, P 5 0.029), suggesting a link with neurometabolic dysregulation. At caudate-putamen, high-fat diet led to a surprising increase in the pool of N-acetylaspartate (P 5 0.028). A relation with metabolic changes was again suggested by the negative correlation between glucose intolerance and levels of glutamatergic metabolites in this region (glutamate, r 5-0.845, P 5 0.014; Glx, r 5-0.834, P 5 0.020). Neither changes in phosphate compounds nor major structural alterations were observed for both regions.
Magnetic Resonance in Medicine, 2013
Purpose-Hypothalamic GABA signaling has been shown to regulate the hormonal response to hypoglycemia in animals. The hypothalamus is a challenging brain region for magnetic resonance spectroscopy (MRS) due to its small size and central location. To investigate the feasibility of measuring GABA in the hypothalamus in humans, ultra-high field MRS was used. Methods-GABA levels in the hypothalamus and occipital cortex (control region) were measured in healthy volunteers during euglycemia and hypoglycemia at 7 tesla using short-echo STEAM (TE=8ms, TR=5s). Results-Hypothalamic GABA levels were quantified with a mean within-session test-retest coefficient of variance of 9%. Relatively high GABA levels were observed in the hypothalamus compared to other brain regions. Hypothalamic GABA levels were 3.5±0.3 µmol/g during euglycemia (glucose 89±6 mg/dL) vs. 3.0±0.4 µmol/g during hypoglycemia (glucose 61±3 mg/dL) (P=0.06, N=7). In the occipital cortex, GABA levels remained constant at 1.4±0.4 vs.1.4±0.3 µmol/g (P=0.3, N=5) as glucose fell from 91±4 to 61±4 mg/dL. Conclusion-GABA concentration can be quantified in the human hypothalamus and shows a trend towards decrease in response to an acute fall in blood glucose. These methods can be used to further investigate role of GABA signaling in the counter regulatory response to hypoglycemia in humans.
Proceedings of the National Academy of Sciences
To determine the relationship between cerebral Glc metabolism and glutamatergic neuronal function, we used 13 C NMR spectroscopy to measure, simultaneously, the rates of the tricarboxylic acid cycle and Gln synthesis in the rat cortex in vivo. From these measurements, we calculated the rates of oxidative Glc metabolism and glutamate-neurotransmitter cycling between neurons and astrocytes (a quantitative measure of glutamatergic neuronal activity). By measuring the rates of the tricarboxylic acid cycle and Gln synthesis over a range of synaptic activity, we have determined the stoichiometry between oxidative Glc metabolism and glutamateneurotransmitter cycling in the cortex to be close to 1:1. This finding indicates that the majority of cortical energy production supports functional (synaptic) glutamatergic neuronal activity. Another implication of this result is that brain activation studies, which map cortical oxidative Glc metabolism, provide a quantitative measure of synaptic glutamate release.
Journal of Neurochemistry, 2012
Chronic hyperglycemia could lead to cerebral metabolic alterations and CNS injury. However, findings of metabolic alterations in poorly managed diabetes in humans and animal models are rather inconsistent. We have characterized the cerebral metabolic consequences of untreated hyperglycemia from the onset to the chronic stage in a streptozotocin-induced rat model of diabetes. In vivo 1 H magnetic resonance spectroscopy (MRS) was used to measure over 20 neurochemicals longitudinally. Upon the onset of hyperglycemia (acute state), increases in brain glucose levels were accompanied by increases in osmolytes and ketone bodies, all of which remained consistently high through the chronic state of over 10 weeks of hyperglycemia. Only after over 4 weeks of hyperglycemia, the levels of other neurochemicals including Nacetylaspartate and glutathione were significantly reduced and these alterations persisted into the chronic stage. However, glucose transport was not altered in chronic hyperglycemia of over 10 weeks. When glucose levels were acutely restored to euglycemia, some neurochemical changes were irreversible, indicating the impact of prolonged uncontrolled hyperglycemia on the CNS. Furthermore, progressive changes in neurochemical levels from control to acute and chronic conditions demonstrated the utility of 1 H MRS as a noninvasive tool in monitoring the disease progression in diabetes.
Journal of Cerebral Blood Flow & Metabolism, 2010
Obesity and type 2 diabetes have reached epidemic proportions; however, scarce information about how these metabolic syndromes influence brain energy and neurotransmitter homeostasis exist. The objective of this study was to elucidate how brain glycogen and neurotransmitter homeostasis are affected by these conditions. [1-13 C]glucose was administered to Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rats. Sprague-Dawley (SprD), Zucker lean (ZL), and ZDF lean rats were used as controls. Several brain regions were analyzed for glycogen levels along with 13 C-labeling and content of glutamate, glutamine, GABA, aspartate, and alanine. Blood glucose concentrations and 13 C enrichment were determined. 13 C-labeling in glutamate was lower in ZO and ZDF rats in comparison with the controls. The molecular carbon labeling (MCL) ratio between alanine and glutamate was higher in the ZDF rats. The MCL ratios of glutamine and glutamate were decreased in the cerebellum of the ZO and the ZDF rats. Glycogen levels were also lower in this region. These results suggest that the obese and type 2 diabetic models were associated with lower brain glucose metabolism. Glucose metabolism through the TCA cycle was more decreased than glycolytic activity. Furthermore, reduced glutamateglutamine cycling was also observed in the obese and type 2 diabetic states.