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Estimation of glucose carbon recycling in children with glycogen storage disease: A 13C NMR study using
B Kalderon1, S H Korman, A Gutman
1Isotope Department, Weizmann Institute of Science, Rehovot, Israel.
Insights
This study developed a stable isotope method to measure glucose recycling in children with glycogen storage diseases. The findings rule out gluconeogenesis in GSD-I but suggest it
Area of Science:
- Biochemistry
- Metabolic Disorders
- Isotope Tracing
Background:
- Glycogen storage disease type I (GSD-I) and type III (GSD-III) are genetic disorders affecting glucose metabolism.
- Patients with GSD-I lack glucose 6-phosphatase, impairing glucose release from the liver.
- Understanding glucose production mechanisms in these diseases is crucial for diagnosis and treatment.
Purpose of the Study:
- To develop and apply a stable isotope procedure for estimating hepatic glucose carbon recycling.
- To elucidate the mechanism of glucose production in patients lacking glucose 6-phosphatase.
- To differentiate glucose production pathways in GSD-I and GSD-III patients.
Main Methods:
- Utilized a stable isotope procedure involving primed dose-constant nasogastric infusion of D-[U-13C]glucose.
- Analyzed hepatic glucose carbon recycling using 13C Nuclear Magnetic Resonance (NMR) spectra.
- Derived recycling parameters from plasma glucose C-1 splitting patterns and enrichment levels, confirmed by gas chromatography/mass spectrometry.
Main Results:
- GSD-I patients showed plasma glucose composition consistent with a mixture of infused 13C-enriched and unlabeled glucose, indicating no recycled glucose.
- Significantly different glucose carbon recycling values were observed in GSD-III patients compared to GSD-I.
- Results exclude gluconeogenesis as a glucose production mechanism in GSD-I children, supporting amylo-1,6-glucosidase activity.
Conclusions:
- The study provides evidence against gluconeogenesis in GSD-I, suggesting alternative glucose release pathways.
- Gluconeogenesis is indicated as the primary route for endogenous glucose synthesis in GSD-III patients.
- The developed stable isotope method shows potential as a noninvasive diagnostic test for inborn errors of gluconeogenesis.
Abstract:
A stable isotope procedure to estimate hepatic glucose carbon recycling and thereby elucidate the mechanism by which glucose is produced in patients lacking glucose 6-phosphatase is described. A total of 10 studies was performed in children with glycogen storage disease type I (GSD-I) and type III (GSD-III) and control subjects. A primed dose-constant nasogastric infusion of D-[U-13C]glucose (greater than 99% 13C-enriched) or an infusion diluted with nonlabeled glucose solution was administered following different periods of fasting. Hepatic glucose carbon recycling was estimated from 13C NMR spectra. The recycling parameters were derived from plasma beta-glucose C-1 splitting pattern, doublet/singlet values of plasma glucose C-1 in comparison to doublet/singlet values of known mixtures of [U-13C]glucose and unlabeled glucose as a function of 13C enrichment of glucose C-1. The fractional glucose C-1 enrichment of plasma glucose samples was analyzed by 1H NMR spectroscopy and confirmed by gas chromatography/mass spectroscopy. The values obtained for GSD-I patients coincided with the standard [U-13C]glucose dilution curve. These results indicate that the plasma glucose of GSD-I subjects comprises only a mixture of 99% 13C-enriched D-[U-13C]glucose and unlabeled glucose but lacks any recycled glucose. Significantly different glucose carbon recycling values were obtained for two GSD-III patients in comparison to GSD-I patients. Our results eliminate a mechanism for glucose production in GSD-I children involving gluconeogenesis. However, glucose release by amylo-1,6-glucosidase activity would result in endogenous glucose production of non-13C-labeled and nonrecycled glucose carbon, as was found in this study. In GSD-III patients gluconeogenesis is suggested as the major route for endogenous glucose synthesis. The contribution of the triose-phosphate pathway in these patients has been determined. The significant difference of the glucose C-1 splitting pattern in plasma GSD-III and control subjects, in comparison to GSD-I plasma, can be used as a parameter for estimating glucose recycling. This approach can be developed as a noninvasive diagnostic test for inborn enzymatic defects involving gluconeogenesis.