Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18F-deoxyglucose positron emission tomography (18F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability. Description Decreased astrocyte-neuron glucose flux in G1D causes epileptogenic oscillations that are modulable by metabolic intervention. Fuel-dependent inhibition Glucose transporter type I deficiency (G1D) is characterized by reduced brain glucose and development of treatment-resistant epilepsy. Here, Rajasekaran et al. use electroencephalography and imaging data from individuals with G1D and showed that the thalamus/sensorimotor cortex circuit might be a critical area involved in the increased brain excitability and the development of seizures. In a mouse model of G1D, the authors showed no energy metabolism impairments, whereas synaptic inhibition of cortical pyramidal and thalamic cells was reduced. Switch in carbon source restored inhibitory activity, and inhibition of AMPA receptor reduced seizures in mice, suggesting that failure of the inhibitory synapses of the circuit might be the main cause of seizure activity in G1D.

Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency

While hemoglobin A1c (HbA1c) is commonly used to monitor therapy response in type 2 diabetes (T2D), GV is emerging as an essential additional metric for optimizing glycemic control. Our goal was to learn more about the impact of hypoglycemic agents on HbA1c levels and GV in patients with T2D. A systematic review and network meta-analysis (NMA) of randomized controlled trials were performed to assess the effects of glucagon-like peptide 1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter (SGLT)-2 inhibitors, dipeptidyl peptidase (DPP)-4 inhibitors, sulfonylurea and thiazolidinediones on Mean Amplitude of Glycemic Excursions (MAGE) and HbA1c. Searches were performed using PubMed and EMBASE. A random-effect model was used in the NMA, and the surface under the cumulative ranking was used to rank comparisons. All studies were checked for quality according to their design and also for heterogeneity before inclusion in this NMA. The highest reduction in MAGE was achieved by GLP-1 RAs (SUCRA 0.83), followed by DPP-4 inhibitors (SUCRA: 0.72), and thiazolidinediones (SUCRA: 0.69). In terms of HbA1c reduction, GLP-1 RAs were the most effective (SUCRA 0.81), followed by DPP-4 inhibitors (SUCRA 0.72) and sulfonylurea (SUCRA 0.65). Our findings indicated that GLP-1 RAs have relatively high efficacy in terms of HbA1c and MAGE reduction when compared with other hypoglycemic agents and can thus have clinical application. Future studies with a larger sample size and appropriate subgroup analyses are warranted to completely understand the glycemic effects of these agents in various patients with T2D. The protocol for this systematic review was registered with the International Prospective Register of Systematic Reviews (CRD42021256363).

Hypoglycemic agents and glycemic variability in individuals with type 2 diabetes: A systematic review and network meta-analysis

Red blood cells circulating through the brain are briefly but closely apposed to the capillary endothelium. We hypothesized that this contact provides a nearly direct pathway for metabolic substrate transfer to neural cells that complements the better characterized plasma to endothelium transfer. While brain function is considered independent of normal fluctuations in blood glucose concentration, this is not borne out by persons with glucose transporter I (GLUT1) deficiency (G1D). In them, encephalopathy is often ameliorated by meal or carbohydrate administration, and this enabled us to test our hypothesis: Since red blood cells contain glucose, and since the red cells of G1D individuals are also deficient in GLUT1, replacing them with normal donor cells via exchange transfusion could augment erythrocyte to neural cell glucose transport via mass action in the setting of unaltered erythrocyte count or plasma glucose abundance. This motivated us to perform red blood cell exchange in 3 G1D persons. There were rapid, favorable and unprecedented changes in cognitive, electroencephalographic and quality-of-life measures. The hypothesized transfer mechanism was further substantiated by in vitro measurement of direct erythrocyte to endothelial cell glucose flux. The results also indicate that the adult intellect is capable of significant enhancement without deliberate practice. ClinicalTrials.gov registration: NCT04137692 https://clinicaltrials.gov/ct2/show/NCT04137692 

Red blood cells as glucose carriers to the human brain: Modulation of cerebral activity by erythrocyte exchange transfusion in Glut1 deficiency (G1D)

Both long-term glycaemic variability and arterial stiffness have been recognized as cardiovascular risk factors. This study aims to investigate whether an association between these phenomena exists in individuals with type 1 diabetes.This cross-sectional study included 673 adults (305 men, 368 women) with type 1 diabetes and combined available retrospective laboratory data on HbA1c from the preceding 10 years with outcome data on arterial stiffness and clinical variables from a comprehensive study visit. HbA1c variability was calculated as adjusted standard deviation (adj-HbA1c-SD), coefficient of variation (HbA1c-CV) and average real variability (HbA1c-ARV). As measures of arterial stiffness, carotid-femoral pulse wave velocity (cfPWV; n = 335) and augmentation index (AIx; n = 653) were assessed using applanation tonometry.The study population had a mean age of 47.1 (± 12.0) years and a median duration of diabetes of 31.2 (21.2-41.3) years. The median number of HbA1c assessments per individual was 17 (12-26). All three indices of HbA1c variability were significantly correlated with both cfPWV and AIx after adjustment for sex and age (p < 0.001). In separate multivariable linear regression models, adj-HbA1c-SD and HbA1c-CV were significantly associated with cfPWV (p = 0.032 and p = 0.046, respectively) and AIx (p = 0.028 and p = 0.049, respectively), even after adjustment for HbA1c-mean. HbA1c-ARV was not associated with cfPWV or AIx in the fully adjusted models.An association independent of HbA1c-mean was found between HbA1c variability and arterial stiffness, suggesting a need to consider multiple HbA1c metrics in studies assessing cardiovascular risk in type 1 diabetes. Longitudinal and interventional studies are needed to confirm any causal relationship and to find strategies for reducing long-term glycaemic variability. 

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Higher HbA1c variability is associated with increased arterial stiffness in individuals with type 1 diabetes

http://manuscript.elsevier.com/S1957255721003102/pdf/S1957255721003102.pdf

Fabrice Bonnet

Papers

Glycaemic variabilities: Key questions in pursuit of clarity.