Methods of stable isotope tracer technology used in studies of flux analysis in IEM
Isotope dilution of an exogenous infused metabolite
Isotope dilution of an endogenously produced metabolite
Oral loading tests
Glycogen storage disease type I
Residual glucose production in patients with GSD Ia in vivo
Glucose metabolism in animal models of GSD Ia and Ib
Lipid metabolism in patients with GSD Ia in vivo
Lipid metabolism in animal model of GSD Ib
Medium-chain acyl-CoA dehydrogenase deficiency
Residual activity of mitochondrial medium-chain fatty acid oxidation in patients with MCAD deficiency in vivo
Animal models of mitochondrial fatty acid oxidation defects
Propionic and methylmalonic aciduria
Propionate metabolism in patients with propionic and methylmalonic aciduria
Propionate metabolism in ex vivo models
Urea cycle defects
Estimation of the urea synthetic flux in vivo in patients with urea cycle defects
Tracer-based studies of nitrogen metabolism in model systems
Tracer-based studies of citrate metabolism in fibroblasts of patients with combined D,L-2-hydroxyglutaric aciduria
Conclusions and future perspectives
- Appreciable postprandial glucose production
- Glucose production is due to glucosidase activity in liver
- Intracellular de novo lipid metabolism is strongly enhanced
- Lipoprotein metabolism seems to be impaired with reduced lipolysis
- Metabolic reprogramming is driven by the transcription factor ChREBP activated by G6P
- Normal oxidation of medium-chain fatty acids.
- The hypoglycemia is driven by a persistent increased consumption of glucose by peripheral tissue and an inadequate production of glucose by gluconeogenesis
- Supply of gluconeogenic substrates by peripheral tissue might be too low.
- A protein-enriched diet might be an additional therapeutic option for patient with MCADD to boost gluconeogenesis to prevent a hypoglycemic hypoketotic crisis.
- There might be an additional role of peroxisomes and endoplasmic reticulum to fatty acid oxidation
- Propionate oxidation is almost higher in patients with PMA than in healthy volunteers
- Gut microbiota are an important producer of propionate
- A modified β oxidation pathway of propionate exists in humans, with cytotoxic intermediates
- Changing the microbiota composition by dietary intervention might be a therapeutic option
- First pass absorption by the liver of ammonia from the gut is ~70% and 30% enters the systemic circulation.
- Direct conversion of ammonia into urea upon first pass is limited to 35% of the supplied ammonia.
- Remainder of supplied ammonia is used in the synthesis of glutamine, in liver and in muscle
- Glutamine is central in whole body nitrogen metabolism and in urea synthesis
- 2-Ketoglutarate supply in hepatic mitochondria is an important precursor in whole body glutamate and glutamine synthesis
- Additional gifts of glutamate to enhance glutamine synthesis during hyperammonemic events might be an additional therapeutic option
- Re-interpretation of changes in glutamine concentration in blood during the monitoring of therapy might be necessary
- There is an as yet unidentified pathway of phenylalanine oxidation.
- Preliminary results in fibroblast point to a shift from glucose to glutamine to support lipid and cholesterol synthesis