Hepatic anaplerotic outflow fluxes are redirected from gluconeogenesis to lactate synthesis in patients with Type 1a glycogen storage disease.
Hepatic glucose production and relative Krebs cycle fluxes (indexed to a citrate synthase flux of 1.0) were evaluated with [U-(13)C]glycerol tracer in 5 fed healthy controls and 5 Type 1a glycogen storage disease (GSD1a) patients. Plasma glucose, hepatic glucose-6-phosphate (G6P) and glutamine (13)C-isotopomers were analyzed by (13)C NMR via blood sampling and chemical biopsy. In healthy subjects, 35+/-14% of plasma glucose originated from hepatic G6P while GSD1a patients had no detectable G6P contribution. Compared to controls, GSD1a patients had an increased fraction of acetyl-CoA from pyruvate (0.5+/-0.2 vs. 0.3+/-0.1, p<0.01), and increased pyruvate recycling fluxes (14.4+/-3.8 vs. 8.7+/-2.8, p<0.05). Despite negligible gluconeogenic flux, net anaplerotic outflow was not significantly different from controls (2.2+/-0.8 vs. 1.3+/-0.5). The enrichment of lactate with (13)C-isotopomers derived from the Krebs cycle suggests that lactate was the main anaplerotic product in GSD1a patients.
Jones
John G
JG
NMR Research Unit, Department of Biochemistry and Center for Neurosciences and Cell Biology, Faculty of Sciences and Technology, University of Coimbra, 3001-401 Coimbra, Portugal. john.jones@netc.pt
Garcia
Paula
P
Barosa
Cristina
C
Delgado
Teresa C
TC
Diogo
Luisa
L
D000105:Acetyl Coenzyme A / Q000378:metabolism; D000293:Adolescent; D002247:Carbon Isotopes / Q000737:chemistry; D002648:Child; D002952:Citric Acid Cycle / Q000502:physiology*; D005260:Female; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D005973:Glutamine / Q000097:blood; D005990:Glycerol / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000378:metabolism*; D006801:Humans; D007773:Lactates / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D019289:Pyruvic Acid / Q000378:metabolism; D055815:Young Adult
D002247:Carbon Isotopes; D007773:Lactates; D005973:Glutamine; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D005952:Glucose-6-Phosphatase; D005947:Glucose; D005990:Glycerol