Dynamic Methods for Childhood Hypoglycemia Phenotyping: A Narrative Review

Abstract

Hypoglycemia results from an imbalance between glucose entering the blood compartment and glucose demand, caused by a defect in the mechanisms regulating postprandial glucose homeostasis. Hypoglycemia represents one of the most common metabolic emergencies in childhood, potentially leading to serious neurologic sequelae, including death. Therefore, appropriate investigation of its specific etiology is paramount to provide adequate diagnosis, specific therapy and prevent its recurrence. In the absence of critical samples for biochemical studies, etiological assessment of children with hypoglycemia may include dynamic methods, such as in vivo functional tests, and continuous glucose monitoring. By providing detailed information on actual glucose fluxes in vivo, proof-of-concept studies have illustrated the potential (clinical) application of dynamic stable isotope techniques to define biochemical and clinical phenotypes of inherited metabolic diseases associated with hypoglycemia. According to the textbooks, individuals with glycogen storage disease type I (GSD I) display the most severe hypoglycemia/fasting intolerance. In this review, three dynamic methods are discussed which may be considered during both diagnostic work-up and monitoring of children with hypoglycemia: 1) functional in vivo tests; 2) in vivo metabolic profiling by continuous glucose monitoring (CGM); 3) stable isotope techniques. Future applications and benefits of dynamic methods in children with hypoglycemia are also discussed.

Endogenous Glucose Production in Patients With Glycogen Storage Disease Type Ia Estimated by Oral D-[6,6-2H2]-glucose

“…Interestingly, in several of the 15 currently registered clinical trials for patients with GSDI, outcome parameters for efficacy have been selected that are counterintuitive or even dangerous, such as controlled fasting challenges. Novel techniques are urgently needed to capture alterations in metabolic flux homeostasis that may better reflect therapeutic changes in pharmacodynamics and pharmacokinetics ( 41 ), such as CGM ( 7 , 14 ), and stable isotope methods ( 9 , 42 ). As glucose R a is directly linked to the underlying enzyme defect in GSDIa, it has the potential to develop into a primary disease activity biomarker as opposed to current biomarkers ( 43 ).…”

“…In theory, stable isotope methods have the potential to monitor EGP in patients with GSDIa in a reliable, longitudinal, minimally invasive, safe fashion ( 9 ). At least 2 major methodological aspects challenge the use of stable isotopes in patients with GSDIa.…”

Continuous glucose monitoring for children with hypoglycaemia: Evidence in 2023

“…Separately, Rossi et al. ( 91 ) propose the use of CGM in a hybrid approach to determine fasting tolerance in children with GSDs rather than the traditional “controlled fast” with multiple fingerprick tests. They go on to highlight the efficacy of CGM to determine incidence of nocturnal hypoglycaemia as well as the impact of diet and medications on glycaemic profiles.…”

Expanding the clinical spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency: novel PCK1 variants in four Arabian Gulf families

“…Normoglycemia is tightly maintained via multiple metabolic pathways such as glycogenolysis, gluconeogenesis, mitochondrial fatty acid oxidation, ketogenesis, and ketolysis [ 2 ]. Disrupting glucose homeostasis due to genetic defects in the pathways responsible for regulating glucose levels can cause hypoglycemia, which can lead to a range of disorders related to inborn errors of metabolism [ 3 ]. Disease causing variants in the PCK1 gene (MIM 614168) lead to cytosolic phosphoenolpyruvate carboxykinase deficiency (MIM 261680).…”