Frequently asked questions (FAQs) about DMI
“Isn’t drinking deuterated or heavy water poisonous for humans?”
No, the amount of deuterated water, glucose or other substrates needed for a typical DMI study are perfectly safe. Studies on human whole body metabolism can use one or two orders of magnitude more deuterated substrate over much longer durations (days to weeks). Studies over more than 30 years have not shown any negative consequences of deuterium administration (Busch et al, Nature Protocols 2, 3045 (2007), Macallan et al, Nature Protocols 4, 1313 (2009), Decaris et al, Hepatology 65, 78 (2017))
The origin of this myth can be traced back to the years immediately following the discovery of deuterium by Urey and coworkers in 1932. Researchers were interested in the biological effects of heavy water. Studies showed that many organisms, from bacteria to eukaryotes, thrived perfectly well in up to 5% heavy water. However, many organisms did not survive water deuteration levels of 50 – 100%, thus starting the myth that heavy water is poisonous when consumed.
A typical DMI study uses a maximum of 60 gram deuterated glucose, which corresponds to circa 0.7 gram of deuterium. Via a number of metabolic pathways and products, the deuterium label ultimately ends up in the body water pool. It thereby raises the body deuterium level from natural abundance (or ~0.015 %) to circa 0.021%.
Another way to put the deuterium load in DMI studies into perspective is to realize that the median lethal dosage (LD50) for heavy water is circa 30% of body mass (or 300 g/kg). As the LD50 for ethanol is 7 g/kg, drinking of heavy water is safer than alcohol consumption
“The information obtained with DMI can also be obtained with 1H MRSI”
As an isotope labeling method DMI fundamentally detects metabolic flow through dynamic metabolic pathways such as the citric acid cycle. The appearance of isotopic label in downstream products proves the existence and activity of a particular pathway at the time of the study. Proton (1H) NMR excels at detecting total metabolic pools. However, since protons in existing and newly formed metabolic products are indistinguishable, proton NMR is incapable of detecting dynamic metabolic pathways in which the total metabolic pools are constant.
The origins of this myth can be found in studies where the 1H NMR and isotopic labeling data demonstrate a strong correlation. A positive example can be found in cancer, where a 1H-MR-based phenotype would be increased lactate and decreased glutamate levels at the advanced stages of the decease. A DMI study would also show increased 2H-labeled lactate and decreased 2H-labeled glutamate levels. However, a strong correlation between 1H and 2H-based data does not imply identical information content.
A simple, but relevant example would be the metabolic state of an ischemic lesion. 1H MRSI would reveal a significant lactate signal throughout the ischemic legion as the lack of oxygen forced the anaerobic breakdown of glucose. A DMI study would show significant 2H-labeled lactate production in the ischemic penumbra, but almost no 2H-labeled lactate appearance in ischemic core. This study has already been performed with 13C isotopic label [4] and would show similar results with 2H isotopic label. Like other isotope labeling methods, DMI provides truly unique information that cannot be obtained with 1H MRSI. However, the DMI results can be enhanced and complimented by 1H MRSI.
[1] Busch et al, Nature Protocols 2, 3045 (2007)
[2] Macallan et al, Nature Protocols 4, 1313 (2009)
[3] Decaris et al, Hepatology 65, 78 (2017)
[4] Dijkhuizen et al, JCBFM 19, 376 (1999)