Exploring diazoxide and continuous glucose monitoring as treatment for Glut1 deficiency syndrome

Logel, Santhi N; Connor, Ellen L.; Hsu, David; Fenske, Rachel J.; Paloian, Neil J.; Vivo, Darryl C. De

doi:10.1002/acn3.51462

Cited by 11 publications

(3 citation statements)

References 26 publications

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“…Logel et al. ( 92 ) similarly used intermittent CGM to initiate and then titrate doses of diazoxide in a patient with Glut1 deficiency who had failed ketogenic diet; without the high granularity data of CGM it was felt that diazoxide would have been administered at incorrect doses, risking the loss of efficacy seen in other cases treated without CGM.…”

Section: Novel Directions and A Possible Future For Cgm In Hypoglycaemiamentioning

confidence: 99%

Continuous glucose monitoring for children with hypoglycaemia: Evidence in 2023

et al. 2023

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In 2023, childhood hypoglycaemia remains a major public health problem and significant risk factor for consequent adverse neurodevelopment. Irrespective of the underlying cause, key elements of clinical management include the detection, prediction and prevention of episodes of hypoglycaemia. These tasks are increasingly served by Continuous Glucose Monitoring (CGM) devices that measure subcutaneous glucose at near-continuous frequency. While the use of CGM in type 1 diabetes is well established, the evidence for widespread use in rare hypoglycaemia disorders is less than convincing. However, in the few years since our last review there have been multiple developments and increased user feedback, requiring a review of clinical application. Despite advances in device technology, point accuracy of CGM remains low for children with non-diabetes hypoglycaemia. Simple provision of CGM devices has not replicated the efficacy seen in those with diabetes and is yet to show benefit. Machine learning techniques for hypoglycaemia prevention have so far failed to demonstrate sufficient prediction accuracy for real world use even in those with diabetes. Furthermore, access to CGM globally is restricted by costs kept high by the commercially-driven speed of technical innovation. Nonetheless, the ability of CGM to digitally phenotype disease groups has led to a better understanding of natural history of disease, facilitated diagnoses and informed changes in clinical management. Large CGM datasets have prompted re-evaluation of hypoglycaemia incidence and facilitated improved trial design. Importantly, an individualised approach and focus on the behavioural determinants of hypoglycaemia has led to real world reduction in hypoglycaemia. In this state of the art review, we critically analyse the updated evidence for use of CGM in non-diabetic childhood hypoglycaemia disorders since 2020 and provide suggestions for qualified use.

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Section: Novel Directions and A Possible Future For Cgm In Hypoglycaemiamentioning

confidence: 99%

Continuous glucose monitoring for children with hypoglycaemia: Evidence in 2023

et al. 2023

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“…Difference in dosages is mainly due to pharmacokinetics and pharmacodynamics changes during the development responsible for agerelated differences in drug disposition. This includes gastric pH, maturity of cytochrome P450 isoforms and single glucuronosyltransferase, apparent volume of distribution, concentration of plasma proteins, glomerular filtration rate and active tubular secretion [18]. Available data from the product drug characteristics indicate that intake dose is quickly absorbed, and highly bounded to plasma proteins (>90%).…”

Section: Pharmacology Of Diazoxidementioning

confidence: 99%

Pulmonary hypertension associated with diazoxide: the SUR1 paradox

Montani,

Antigny,

Jutant

et al. 2023

ERJ Open Res

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The ATP-sensitive potassium channels (KATP) and their regulatory subunits, sulfonylurea receptor 1 (SUR1/Kir6.2) and SUR2/Kir6.1, contribute to the pathophysiology of pulmonary hypertension (PH). Loss-of-function pathogenic variants in theABCC8gene, which encodes for SUR1, have been associated with heritable pulmonary arterial hypertension. Conversely, activation of SUR1 and SUR2 leads to the relaxation of pulmonary arteries and reduces cell proliferation and migration. Diazoxide, a SUR1 activator, has been shown to alleviate experimental PH, suggesting its potential as a therapeutic option. However, there are paradoxical reports of diazoxide-induced PH in infants.This review explores the role of SUR1/2 in the pathophysiology of PH and the contradictory effects of diazoxide on the pulmonary vascular bed.Additionally, we conducted a comprehensive literature review of cases of diazoxide-associated PH and analyzed data from the WHO pharmacovigilance database (Vigibase). Significant disproportionality signals linking diazoxide to PH, while no other SUR activators have been connected with pulmonary vascular disease. Diazoxide-associated PH seems to be dose-dependent and potentially related to acute effects on the pulmonary vascular bed. Further research is required to decipher the differing pulmonary vascular consequences of diazoxide in different age populations and experimental models.

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“…Diazoxide administration (a medication used to treat low blood sugar, interfering with insulin release through its action on potassium channels) was proposed to contribute to raising the blood and CSF glucose levels in a patient with Glut1DS who did not respond to a KD. This provides a higher level of glucose in CSF, and clinical improvement, being a reliable long-term treatment when associated with continuous glucose monitoring [ 66 ].…”

Section: Treatment Prognosis and Researchmentioning

confidence: 99%

One Molecule for Mental Nourishment and More: Glucose Transporter Type 1—Biology and Deficiency Syndrome

et al. 2022

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Glucose transporter type 1 (Glut1) is the main transporter involved in the cellular uptake of glucose into many tissues, and is highly expressed in the brain and in erythrocytes. Glut1 deficiency syndrome is caused mainly by mutations of the SLC2A1 gene, impairing passive glucose transport across the blood–brain barrier. All age groups, from infants to adults, may be affected, with age-specific symptoms. In its classic form, the syndrome presents as an early-onset drug-resistant metabolic epileptic encephalopathy with a complex movement disorder and developmental delay. In later-onset forms, complex motor disorder predominates, with dystonia, ataxia, chorea or spasticity, often triggered by fasting. Diagnosis is confirmed by hypoglycorrhachia (below 45 mg/dL) with normal blood glucose, 18F-fluorodeoxyglucose positron emission tomography, and genetic analysis showing pathogenic SLC2A1 variants. There are also ongoing positive studies on erythrocytes’ Glut1 surface expression using flow cytometry. The standard treatment still consists of ketogenic therapies supplying ketones as alternative brain fuel. Anaplerotic substances may provide alternative energy sources. Understanding the complex interactions of Glut1 with other tissues, its signaling function for brain angiogenesis and gliosis, and the complex regulation of glucose transportation, including compensatory mechanisms in different tissues, will hopefully advance therapy. Ongoing research for future interventions is focusing on small molecules to restore Glut1, metabolic stimulation, and SLC2A1 transfer strategies. Newborn screening, early identification and treatment could minimize the neurodevelopmental disease consequences. Furthermore, understanding Glut1 relative deficiency or inhibition in inflammation, neurodegenerative disorders, and viral infections including COVID-19 and other settings could provide clues for future therapeutic approaches.

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Exploring diazoxide and continuous glucose monitoring as treatment for Glut1 deficiency syndrome

Cited by 11 publications

References 26 publications

Continuous glucose monitoring for children with hypoglycaemia: Evidence in 2023

Continuous glucose monitoring for children with hypoglycaemia: Evidence in 2023

Pulmonary hypertension associated with diazoxide: the SUR1 paradox

One Molecule for Mental Nourishment and More: Glucose Transporter Type 1—Biology and Deficiency Syndrome

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