Problems With Glutamine Research

A lot of these cell culture experiments showing the effects of exogenous glutamine, in the presence or absence of other substrates, are using these "luxuriant," as some authors describe "abundance" as being, concentrations of extracellular glutamine, such as 5 mM (http://scholar.google.com/scholar?q=glutamine+%225+mM%22&hl=en&lr=) or, more commonly, 2 mM (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=glutamine+%222+mM%22). Those are very high concentrations, and the extracellular fluid glutamine concentration in the brain is 400-1300 uM or so, which is 0.4-1.3 mM. I think there can be a tendency to do cell culture research and assume that cells in vivo are getting these abundant supplies of substrates, but it's not necessarily the case. I've seen that in research on magnesium, in which researchers explicitly assume that all of the ATP in vivo is going to be MgATP(2-). It's not the case, in my opinion. Also, most of the research on glutamine in humans has been done in people who have not been receiving any source of exogenous glutamine, and this is a major issue. Part of this has to do with the assumption that glutamine does not enter the brain, but there's considerable evidence that it does. The rate of efflux from the brain is almost always higher than the rate of uptake into the brain, but that says nothing about the extent to which glutamine can enter the brain. Neither does the absence of a discernable "spike" or increase in the ECF glutamine concentration, in response to the infusion of intravenous glutamine, provide any information about the extent to which glutamine has entered the brain. The glutamine-glutamate cycle is very dynamic and flexible and tends to adapt to sources of exogenous glutamine. This means that, for example, the glutamine is converted into glutamate and then either directly into 2-oxoglutarate, by glutamate dehydrogenase, or transaminated, with oxaloacetate, into 2-oxoglutarate (2-OG) and aspartate. The 2-OG can then be oxidized in the tricarboxylic acid (TCA) cycle, and its carbons can appear in all TCA cycle intermediates and in acetyl-CoA also, etc. Yudkoff et al. (1988) [Yudkoff et al., 1988: (http://www.ncbi.nlm.nih.gov/pubmed/2900878)] found that a physiological concentraion of extracellular glutamine (500 uM) caused cultured astrocytes to demonstrate no net utilization or synthesis of glutamine, and a supraphysiological concentration of 5 mM (5000 uM) was required to show a net utilization of glutamine by astrocytes. They had to remove all glutamine from the culture medium to cause the astrocytes to show a net synthesis of glutamine. The rate of synthesis is not the same thing as the rate of export, but I'm not going to get into all of that. This seems strange, but they're talking about utilization of labeled glutamine. Similarly, exogenous glutamine can spare the utilization of the existing glutamate pool for glutamine synthesis and not even elevate the total intracellular glutamate concentration [Qu et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11746415)]. These and other articles tend to suggest that, following ischemia, for example, the drastic increases in the oxidation of 2-OG are likely to cause exogenous glutamine to appear to exert no effect on the brain. I've discussed other mechanisms that suggest this, in recent postings. In other articles, researchers have noted that very few sites in the body demonstrate a *net* formation of glutamine, meaning that the rate of export from the tissue or cell group at large is higher than the rate of utilization of glutamine. A lot of research portrays the glutamine-glutamate-GABA cycle as if it's constantly generating all this glutamine and that there's endless glutamine being supplied and that cells can't oxidize more than 5 percent and can't even use all of it, because there's so much of it, or whatever. But large amounts of ATP are constantly being used up to maintain the cycle, and the amount of superfluous glutamine is likely to be quite small in many tissues, especially in trauma patients, etc.