Doubly labeled water
Doubly labeled water is water in which both the hydrogen and the oxygen have been partly or completely replaced (i.e. labeled) with an uncommon isotope of these elements for tracing purposes.
In practice, for both practical and safety reasons, almost all recent applications of the "doubly labeled water" method use water labeled with heavy but non-radioactive forms of each element (deuterium and oxygen-18). In theory, radioactive heavy isotopes of the elements could be used for such labeling; this was the case in many early applications of the method.
In particular, doubly labeled water (DLW) can be used for a method to measure the average daily metabolic rate of an organism over a period of time (often also called the Field metabolic rate, or FMR, in non-human animals). This is done by administering a dose of DLW, then measuring the elimination rates of deuterium and oxygen-18 in the subject over time (through regular sampling of heavy isotope concentrations in body water, by sampling saliva, urine, or blood). At least two samples are required: an initial sample (after the isotopes have reached equilibrium in the body), and a second sample some time later. The time between these samples depends on the size of the animal. In small animals, the period may be as short as 24 hours; in larger animals (such as adult humans), the period may be as long as 14 days.
The method was invented in the 1950s by Nathan Lifson and colleagues at the University of Minnesota. However, its use was restricted to small animals until the 1980s because of the high cost of the oxygen-18 isotope. Advances in mass spectrometry during the 1970s and early 1980s reduced the amount of isotope required, which made it feasible to apply the method to larger animals, including humans. The first application to humans was in 1982, by Dale Schoeller, over 25 years after the method was initially discovered. A complete summary of the technique is provided in a book by British biologist John Speakman.
The technique measures a subject's carbon dioxide production during the interval between first and last body water samples. The method depends on the details of carbon metabolism in our bodies. When cellular respiration breaks down carbon-containing molecules to release energy, carbon dioxide is released as a byproduct. Carbon dioxide contains two oxygen atoms and only one carbon atom, but food molecules such as carbohydrates do not contain enough oxygen to provide both oxygen atoms found in CO2. It turns out, one of the two oxygen atoms in CO2 is derived from body water. If the oxygen in water is labeled with 18O, then CO2 produced by respiration will contain labeled oxygen. In addition, as CO2 travels from the site of respiration through the cytoplasm of a cell, through the interstitial fluids, into the bloodstream and then to the lungs some of it is reversibly converted to bicarbonate. So, after consuming water labeled with 18O, the 18O equilibrates with the body's bicarbonate and dissolved carbon dioxide pool (through the action of the enzyme carbonic anhydrase). As carbon dioxide is exhaled, 18O is lost from the body. This was discovered by Lifson in 1949. However, 18O is also lost through body water loss (such as urine and evaporation of fluids). However, deuterium (the second label in the doubly labeled water) is lost only when body water is lost. Thus the loss of deuterium in body water over time can be used to mathematically compensate for the loss of 18O by the water-loss route. This leaves only the remaining net loss of 18O in carbon dioxide. This measurement of the amount of carbon dioxide lost is an excellent estimate for total carbon dioxide production. Once this is known, the total metabolic rate may be estimated from simplifying assumptions regarding the ratio of oxygen used in metabolism (and therefore heat generated), to carbon dioxide eliminated (see respiratory quotient). This quotient can be measured in other ways, and almost always has a value between 0.7 and 1.0, and for a mixed diet is usually about 0.8.
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