The authors of this article [White and Wilson, 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2306121)] discussed the fact that inorganic phosphate (Pi) antagonizes the inhibitory effect of glucose-6-phosphate on hexokinase activity, and the net result of an increase in the free, intracellular Pi concentration is likely to be an increase in hexokinase activity. The authors of some of these articles make statements that imply or "state" that hexokinase activity is tightly regulated, but that type of statement is invariably based on the assumption that "adequate" or saturating concentrations of magnesium, Pi, and other regulatory factors (such as purine nucleotides, given that MgADP(-), MgATP(2-), Mg2+ itself, and other nucleotides, alone or complexed with Mg2+, regulate hexokinase activity in complex ways by binding to the multiple nucleotide or other-anion binding sites on the enzyme) will exist in cells. Many authors explicitly state that they're making that sort of assumption, and it's unlikely to be valid, in many cases. Magnesium deficiency is known to be widespread, and it's likely, in my opinion, that intracellular Pi depletion is also common. It's interesting that magnesium is an allosteric activator of hexokinase, and magnesium also influences the numbers of allosteric sites that MgATP(2-) can be bound to and the affinity of the binding of MgATP(2-) to hexokinase as a substrate [Bachelard, 1971: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1178047&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/5158910)]. That's a complex and somewhat confusing article, in part because the author reported some of the data in terms of the "Mg2+/ATP ratio, and it can be difficult to understand if the author is saying that an excess of Mg2+ is going to be bound to the enzyme as a free cation or what exactly the concentrations of the individual species are going to be.
In spite of the complexity, exogenous magnesium generally is going to produce effects that are consistent with an increase in hexokinase activity and in the overall rate of glycolytic activity, in my opinion, and that could reasonably be expected to increase intracellular Pi. Magnesium could also tend to increase the sequestration of Pi in glucose-6-phosphate but could also conceivably lead to an increase in Pi turnover, over time (such as by inducing changes in the intracellular pH, as a result of the increases in the activities of glycolytic enzymes). It's interesting that an important mechanism leading to an increase in phosphate uptake into cells is an insulin-induced increase in hexokinase activity [Siddiqui and Bertorini, 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9572247)], and the extra intracellular Pi would have the potential to further activate hexokinase and other glycolytic enzymes. This would be fine, assuming that the extracellular Pi levels are not going to fluctuate wildly and decrease, in response to this type of insulin-induced, somewhat-tissue-specific increase in Pi transport into cells. But it's possible to see the way the manifestations of intracellular Pi depletion (and intracellular Pi depletion itself) could be elusive. There tend to be these strange effects, whereby the factors that are detrimental to Pi homeostasis (i.e. insulin-induced hypophosphatemia) in the short term (or in specific contexts or across multiple organs) are beneficial in the long term and overlap with the effects of Pi itself in complex ways. Assuming that an increase in intracellular Pi enhances insulin sensitivity and activates hexokinase (Pi probably increases insulin sensitivity, in part, *by* activating hexokinase) and other glycolytic enzymes, then would the increase in insulin sensitivity have the potential to further increase Pi uptake and decrease serum Pi in pathological ways, under some circumstances? There was that article I cited, in a recent posting, showing that the postprandial urinary excretion of Pi was inversely correlated with insulin sensitivity, but, presumably that wouldn't always be the case. I wonder if hypophosphatemia or wild swings in intracellular and extracellular Pi might occur, in the short term, in response to the introduction of intensive insulin therapy and contribute to the short-term worsening of neuropathy and other disease processes in people who have diabetes [Leow et al., 2005: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artinstid=1743196&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15701742)]. Even though that type of protocol for administering insulin tends to be beneficial in the long term, there can be short term issues and transient worsening of neuropathy, etc., in some people.
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