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Energy and Structure: Phosphorus

Short post.

Ah, phosphorus. Sounds like the name of a Greek mythology character. Before I discuss glucose and carbon dioxide in response to some comments on the last post, I wanted to discuss a bit about phosphorus.

Meat is good, especially ruminant meat, all the bits you love and all the bits that induce a gag reflex, especially when you can get a hold of the grass fed sorts.

Phosphorus is important.

ATP is good. Adenosine triphosphate.

A lot of readers who read this blog are concerned about calcium and phosphorus. There is this thought pattern that less phosphate is better, which leads to phosphate is harmful, which eventually leads to a less is more type of mentality i.e. restriction.

Your ability to produce ATP is pretty important. You don’t just consume glucose and then phosphate appears from nowhere. It has to come from somewhere. Bad things happen when you eat a lot of carbohydrate and there is a lack of phosphorous in the diet, as carbohydrate places a demand on hexokinase, which requires phosphate to bind glucose to phosphate (glucose-6-phosphate) during glycolysis.

What happens when you are fed a phosphorus deficient diet? (Hettleman, Sabina, Drezner, Holmes, & Swain, 1983; Kilic, Demirkol, Ucsel, Citak, & Karabocuoglu, 2012)

Since the amount of phosphorous in your food is going to have an impact on ATP production, and ATP is the energy currency of cells, you can expect that a deficiency is going to systematically effect the entire organism. Indeed that is what we see in hypophosphatemia: weakness, bone pain, increased susceptibility to infection, numbness and tingling of the extremities, appetite suppression, cold extremities, difficulty swallowing, and a host of other “hypo” like symptoms.

Aside: Fructose is particularly effective at wasting phosphorus as well as inhibiting the absorption of calcium (Bergstra, Lemmens, & Beynen, 1993; Burch et al., 1980; Douard et al., 2010, 2013; Kizhner & Werman, 2002).

References

Bergstra, A. E., Lemmens, A. G., & Beynen, A. C. (1993). Dietary fructose vs. glucose stimulates nephrocalcinogenesis in female rats. The Journal of nutrition, 123(7), 1320–7. Retrieved from http://europepmc.org/abstract/MED/8320569

The effect of dietary fructose vs. glucose on kidney calcification (nephrocalcinosis) was studied in female rats. Fructose or glucose was incorporated into purified diets formulated either according to the nutrient requirements of rats or made nephrocalcinogenic by the addition of phosphorus (19.4 instead of 12.9 mmol/100 g diet) or by restriction of magnesium (0.8 instead of 1.6 mmol/100 g diet). Irrespective of the background composition of the diet, fructose consistently produced higher kidney calcium concentrations than did glucose. Fructose also raised kidney weight, expressed either as wet weight relative to body weight or as absolute dry weight; this greater kidney weight was not explained by the extra calcium. Fructose generally induced greater urinary concentrations of phosphorus and magnesium and lowered urinary pH compared with glucose. The greater urinary phosphorus concentrations in rats fed fructose may be responsible for the nephrocalcinogenic activity of this monosaccharide. Fructose stimulated the absorption of phosphorus and magnesium, which explains the higher concentrations of these minerals in the urine.

Burch, H. B., Choi, S., Dence, C. N., Alvey, T. R., Cole, B. R., & Lowry, O. H. (1980). Metabolic effects of large fructose loads in different parts of the rat nephron. The Journal of biological chemistry, 255(17), 8239–44. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/6773936

Rats were given large parenteral loads of fructose and the different segments of single nephrons then analyzed for fructose metabolites, fructose metabolizing enzymes, and nucleotide high energy phosphates. Fructokinase and fructose-1-P aldolase activities, and all the major metabolite and nucleotide effects, were confined to the proximal tubule. The proximal straight segment had the highest fructokinase and suffered the greatest changes. In this segment, fructose-1-P rose to 60 mmol/kg (dry weight basis) and glycerol-3-P and glucose-6-P reached 8 and 12 mmol/kg, respectively. ATP fell 80% and GTP (judging from the changes in GTP plus GDP) fell by the same percentage, but UTP was less affected. Total adenylate decreased 50%. In the proximal convoluted tubule, where fructokinase was lower and fructose-1-P aldolase higher than in the straight segment, fructose-1-P rose ony one-fourth as much and glucose-6-P was almost unchanged. In contrast, glycerol-3-P rose more, reaching 16 mmol/kg. Other substances measured along the nephron were glycerol-3-P dehydrogenase, fructose-1,6-bisphosphate aldolase, fructose, glucose, fructose bisphosphate, triose phosphate, and 6-P-gluconate. Control ATP levels were found to be highest in the distal tubule.

Douard, V., Asgerally, A., Sabbagh, Y., Sugiura, S., Shapses, S. A., Casirola, D., & Ferraris, R. P. (2010). Dietary fructose inhibits intestinal calcium absorption and induces vitamin D insufficiency in CKD. Journal of the American Society of Nephrology : JASN, 21(2), 261–71. doi:10.1681/ASN.2009080795

Renal disease leads to perturbations in calcium and phosphate homeostasis and vitamin D metabolism. Dietary fructose aggravates chronic kidney disease (CKD), but whether it also worsens CKD-induced derangements in calcium and phosphate homeostasis is unknown. Here, we fed rats diets containing 60% glucose or fructose for 1 mo beginning 6 wk after 5/6 nephrectomy or sham operation. Nephrectomized rats had markedly greater kidney weight, blood urea nitrogen, and serum levels of creatinine, phosphate, and calcium-phosphate product; dietary fructose significantly exacerbated all of these outcomes. Expression and activity of intestinal phosphate transporter, which did not change after nephrectomy or dietary fructose, did not correlate with hyperphosphatemia in 5/6-nephrectomized rats. Intestinal transport of calcium, however, decreased with dietary fructose, probably because of fructose-mediated downregulation of calbindin 9k. Serum calcium levels, however, were unaffected by nephrectomy and diet. Finally, only 5/6-nephrectomized rats that received dietary fructose demonstrated marked reductions in 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) levels, despite upregulation of 1alpha-hydroxylase. In summary, excess dietary fructose inhibits intestinal calcium absorption, induces marked vitamin D insufficiency in CKD, and exacerbates other classical symptoms of the disease. Future studies should evaluate the relevance of monitoring fructose consumption in patients with CKD.

Douard, V., Sabbagh, Y., Lee, J., Patel, C., Kemp, F. W., Bogden, J. D., … Ferraris, R. P. (2013). Excessive fructose intake causes 1,25-(OH)(2)D(3)-dependent inhibition of intestinal and renal calcium transport in growing rats. American journal of physiology. Endocrinology and metabolism, 304(12), E1303–13. doi:10.1152/ajpendo.00582.2012

We recently discovered that chronic high fructose intake by lactating rats prevented adaptive increases in rates of active intestinal Ca(2+) transport and in levels of 1,25-(OH)2D3, the active form of vitamin D. Since sufficient Ca(2+) absorption is essential for skeletal growth, our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children. We tested the hypothesis that 1,25-(OH)2D3 mediates the inhibitory effect of excessive fructose intake on active Ca(2+) transport. First, compared with those fed glucose or starch, growing rats fed fructose for 4 wk had a marked reduction in intestinal Ca(2+) transport rate as well as in expression of intestinal and renal Ca(2+) transporters that was tightly associated with decreases in circulating levels of 1,25-(OH)2D3, bone length, and total bone ash weight but not with serum parathyroid hormone (PTH). Dietary fructose increased the expression of 24-hydroxylase (CYP24A1) and decreased that of 1α-hydroxylase (CYP27B1), suggesting that fructose might enhance the renal catabolism and impair the synthesis, respectively, of 1,25-(OH)2D3. Serum FGF23, which is secreted by osteocytes and inhibits CYP27B1 expression, was upregulated, suggesting a potential role of bone in mediating the fructose effects on 1,25-(OH)2D3 synthesis. Second, 1,25-(OH)2D3 treatment rescued the fructose effect and normalized intestinal and renal Ca(2+) transporter expression. The mechanism underlying the deleterious effect of excessive fructose intake on intestinal and renal Ca(2+) transporters is a reduction in serum levels of 1,25-(OH)2D3. This finding is significant because of the large amounts of fructose now consumed by Americans increasingly vulnerable to Ca(2+) and vitamin D deficiency.

Hettleman, B. D., Sabina, R. L., Drezner, M. K., Holmes, E. W., & Swain, J. L. (1983). Defective adenosine triphosphate synthesis. An explanation for skeletal muscle dysfunction in phosphate-deficient mice. The Journal of clinical investigation, 72(2), 582–9. doi:10.1172/JCI111006

The basis for skeletal muscle dysfunction in phosphate-deficient patients and animals is not known, but it is hypothesized that intracellular phosphate deficiency leads to a defect in ATP synthesis. To test this hypothesis, changes in muscle function and nucleotide metabolism were studied in an animal model of hypophosphatemia. Mice were made hypophosphatemic through restriction of dietary phosphate intake. Gastrocnemius function was assessed in situ by recording isometric tension developed after stimulation of the nerve innervating this muscle. Changes in purine nucleotide, nucleoside, and base content of the muscle were quantitated at several time points during stimulation and recovery. Serum concentration and skeletal muscle content of phosphorous are reduced by 55 and 45%, respectively, in the dietary restricted animals. The gastrocnemius muscle of the phosphate-deficient mice fatigues more rapidly compared with control mice. ATP and creatine phosphate content fall to a comparable extent during fatigue in the muscle from both groups of animals; AMP, inosine, and hypoxanthine (indices of ATP catabolism) appear in higher concentration in the muscle of phosphate-deficient animals. Since total ATP use in contracting muscle is closely linked to total developed tension, we conclude that the comparable drop in ATP content in association with a more rapid loss of tension is best explained by a slower rate of ATP synthesis in the muscle of phosphate-deficient animals. During the period of recovery after muscle stimulation, ATP use for contraction is minimal, since the muscle is at rest. In the recovery period, ATP content returns to resting levels more slowly in the phosphate-deficient than in the control animals. In association with the slower rate of ATP repletion, the precursors inosine monophosphate and AMP remain elevated for a longer period of time in the muscle of phosphate-deficient animals. The slower rate of ATP repletion correlates with delayed return of normal muscle contractility in the phosphate-deficient mice. These studies suggest that the slower rate of repletion of the ATP pool may be the consequence of a slower rate of ATP synthesis and this is in part responsible for the delayed recovery of normal muscle contractility.

Kilic, O., Demirkol, D., Ucsel, R., Citak, A., & Karabocuoglu, M. (2012). Hypophosphatemia and its clinical implications in critically ill children: a retrospective study. Journal of critical care, 27(5), 474–9. doi:10.1016/j.jcrc.2012.03.005

PURPOSE: The aims of this study were to determine the prevalence of hypophosphatemia and to discuss the clinical implications of hypophosphatemia in critically ill children. MATERIALS AND METHODS: A retrospective review of the medical records of children admitted to the pediatric intensive care unit from December 2006 to December 2007 was conducted. RESULTS: In 60.2% (n = 71) of the patients, any serum phosphorous level at admission and at the third day or seventh day after admission to pediatric intensive care unit was in hypophosphatemic range. Sepsis was present in 22.9% (n = 27) of the children studied and was associated with hypophosphatemia (P = .02). Hypophosphatemia was also associated with use of furosemide (P = .04), use of steroid (P = .04), use of β(2) agonist (P = .026), and use of an H(2) blocker (P = .004). There was a significant association between hypophosphatemia and the rate to attain target caloric requirements by enteral route (P = .007). The median time to attain target caloric requirements by enteral route was 2.9 ± 1.9 (0.2-10) days in the normophosphatemic group and 4.4 ± 2.8 (0.3-12) days in the hypophosphatemic group. In the multiple regression model, solely the rate to attain the target caloric requirements by enteral route demonstrated independent association with hypophosphatemia (P = .006; β = .27; 95% confidence interval, 0.02-0.09). Significant association was found between hypophosphatemia and the duration of mechanical ventilation and between hypophosphatemia and pediatric intensive care unit length of stay (P = .02 and P = .001, respectively). CONCLUSIONS: Critically ill pediatric patients are prone to hypophosphatemia, especially if they cannot be fed early by enteral route. Hypophosphatemia is associated with an increased duration of mechanical ventilation and increased length of stay in the pediatric intensive care unit, suggesting that active repletion might improve these parameters.

Kizhner, T., & Werman, M. J. (2002). Long-term fructose intake: biochemical consequences and altered renal histology in the male rat. Metabolism: clinical and experimental, 51(12), 1538–47. doi:10.1053/meta.2002.36306

The use of fructose as a pure sugar has considerably increased in the last 3 decades, especially as a sweetener in carbonated beverages. Our previous studies showed that long-term fructose intake adversely affected several age-related metabolic parameters. The purpose of the present study was to compare the consequences of long-term fructose intake with those of glucose or sucrose on renal morphology and on several biochemical parameters used to estimate renal function. Male rats were fed a commercial diet for 16 months, and had free access either to water (control) or to 250 g/L solutions of fructose, glucose, or sucrose. Fructose-drinking rats exhibited higher liver weights compare to the other dietary groups. Control rats excreted significantly less urinary output than all sugar groups, which did not differ from each other. No differences were observed in fasting plasma fructose, glucose, and creatinine levels, or in urinary glucose levels. Fructose consumption resulted in elevated urinary fructose levels, higher creatinine clearance, and marked proteinuria. The tested sugars had influence on the molecular weight distribution of urinary proteins in the ranges of 10 to 16, 25 to 35, and 75 to 85 kd. Histological examination revealed that fructose consumption led to the formation of foci of cortical tubular necrosis with chronic inflammatory infiltrate, accumulation of tubular hyaline casts, thickening of the Bowman’s capsule, mesangial thickening due to collagen deposits, and the occurrence of hemosiderin in tubular cells. These data suggest that fructose has a negative impact on kidney function and morphology. Further research is required to elucidate the precise mechanisms by which long-term fructose consumption hampers renal metabolism.

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