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Original Studies |
Explorations Fonctionnelles Rénales Métaboliques et Endocriniennes et Laboratoire de Physiologie, Centre Hospitalier Universitaire, Besançon, France
Address all correspondence and requests for reprints to: Dr. Uyen N. Nguyen, Explorations Fonctionnelles Rénales et Métaboliques, Hôpital Jean Minjoz, boulevard Fleming, 25030 Besançon France.
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Abstract |
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Introduction |
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It has been consistently observed in previous studies that glucose ingestion markedly increases the urinary excretion of calcium (2, 3, 4, 5). This increased calciuria has commonly been ascribed to the glucose-induced rise in plasma insulin, which, in turn, impairs renal calcium reabsorption (6, 7). An oral glucose load also causes a slight increase in the urinary excretion of oxalic acid (8). Thus, the ingestion of natural carbohydrates increases the excretion of the two main determinants of urinary calcium-oxalate saturation.
As many people frequently consume aspartame-sweetened soft drinks, it seemed worthwhile to assess how this use of aspartame affects calcium-oxalate metabolism. The present study was therefore designed to investigate the effects of the acute ingestion of 250 mg aspartame on calcium and oxalate metabolisms. This amount of sweetener approximated that contained in two thirds of a liter of sugar-free soft drink. The results were compared to those produced by the ingestion of 75 g glucose, which provides a comparable degree of sweetness and well known metabolic changes.
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Subjects and Methods |
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Seven healthy subjects (four men and three women; normal body mass index; aged 30–47 yr) volunteered for the study. Clinical examination was normal, and no subject had any history of diabetes mellitus, bone disorders, or renal stone disease.
The protocol was approved by the ethical committee of our university hospital, and informed consent was obtained from all subjects after full explanation of the study.
Design of the study
Each subject was studied on 2 experimental days, randomly allocated and spaced 1 week apart. Subjects were instructed to avoid drugs and nutrients known to affect glucose, calcium, phosphorus, or oxalate metabolism. They were asked to abstain from intense physical exercise, ingesting alcohol for 24 h, drinking tea or coffee, and smoking for 12 h before each experimental day. Subjects fasted for 12 h before each experiment, except for drinking 250 mL of very slightly mineralized water (Ca = 0.25 mmol/L; Volvic, Volvic, France) at 0700 h. This water was also used throughout the experiment. When they arrived at the laboratory at 0800 h, they emptied their bladder, drank 250 mL water, and assumed a supine position. An indwelling cannula was inserted in the antecubital vein. After a 60-min baseline period, urine and blood samples were collected. Subjects drank either 250 mg aspartame or 75 g glucose, dissolved in 250 mL water. To ensure sufficient diuresis, subjects drank 200 mL water every hour.
Subjects urinated hourly at 0900, 1000, 1100, and 1200 h into separate containers. From each sample, 10 mL were used for measuring calcium, phosphate, and creatinine levels. Hydrochloric acid was added to the remaining sample to adjust the pH to 2 and was stored at -20 C for subsequent measurement of urinary oxalic acid concentration. Blood samples were taken at the end of the baseline period and every 30 min until the end of the experimental period. Sera were frozen at -20 C for later analysis of glucose, insulin, calcium, phosphate, and creatinine.
Analytical methods
Glucose, calcium, and phosphorus were measured by a colorimetric method with a multitest analyzer (Eris 6170, Eppendorf, Hamburg, Germany). Urinary oxalate was precipitated with calcium sulfate in a water-alcoholic environment and subsequently measured by an enzymatic method using oxalate oxidase (9) (Medela-Biorea, Brussels, Belgium; the interassay coefficient of variation was 7.0%). Serum insulin concentrations were measured by RIA (Phadeseph Insulin RIA, Pharmacia Diagnostics, Uppsala Sweden; the interassay coefficient of variation was 7.7%).
Statistical analysis
Two-way ANOVA with repeated measures was used to assess changes over time. Student’s paired t tests were also used to compare specific series (e.g. comparison of baseline values between the two situations and maximum values to baseline in each situation).
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Results |
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Carbohydrate metabolism (Fig. 1
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Glycemia did not change after aspartame load, whereas after glucose ingestion, it clearly rose from a basal value of 5.46 ± 0.11 to 8.98 ± 0.41 mmol/L at 30 min (P < 0.001), resumed baseline values by 120 min, and then decreased to 4.62 ± 0.31 mmol/L at the end of the test (P < 0.05 compared to the fasting value). Glycemia was higher after glucose load than after aspartame at both 30 and 60 min (P < 0.001), but was lower at the end of the test (P < 0.05).
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Calcium, phosphate, and oxalic acid
Plasma values (Fig. 1
). Calcemia increased after ingestion of
both aspartame and glucose from 2.27 ± 0.02 to 2.32 ± 0.01
mmol/L at 30 min (P < 0.05) and from 2.25 ± 0.01
to 2.29 ± 0.02 mmol/L at 90 min (P < 0.05),
respectively. The increase in calcemia lasted until the end of
aspartame ingestion (P < 0.05), whereas after the
glucose load, calcemia resumed basal values after 150 min. The increase
in calcemia was not significantly different after either aspartame or
glucose, and the trend for a difference in the average calcemia of the
two groups at 150 and 180 min did not reach statistical
significance.
Phosphatemia decreased after both aspartame and glucose intake from 1.25 ± 0.04 to 1.15 ± 0.04 mmol/L (P < 0.01) at 90 min and from 1.25 ± 0.05 to 1.04 ± 0.05 mmol/L (P < 0.01) at 60 min, respectively. The decrease in phosphatemia was greater after glucose load (P < 0.05) at 60 min and remained significantly below baseline values until the end of the survey.
Urinary values (Fig. 2).
Calciuria rose markedly 120 min after the ingestion of both aspartame
and glucose from 70.9 ± 10.0 to 132.1 ± 15.4 µmol/h
(P < 0.01) and from 87.4 ± 12.7 to 195.4 ±
35.0 µmol/h (P < 0.01), respectively. The increase
in calciuria was not significantly different after glucose from that
after aspartame load.
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Oxaluria did not change after aspartame intake, whereas it increased after glucose ingestion from 97.3 ± 9.4 µmol/h (baseline value) to 123.1 ± 12.4 (P < 0.05) at 60 min and 118.1 ± 14.6 (P < 0.05) at 120 min.
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Discussion |
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The amount of aspartame approximated that contained in two thirds of a liter of a sugar-free drink. The sweetening effect was comparable to that of a standard 75-g glucose ingestion, for which the metabolic changes are well documented.
Increased calciuria has been repeatedly described within the 3 h after a glucose load (8, 10, 11). In subjects fasting for 12 h, changes of this magnitude cannot be ascribed to diurnal variations or to the recumbent position (12, 13, 14). In our study, the ingestion of both aspartame and glucose induced a similar, but striking, increase in urinary excretion of calcium that may be linked at least partly to the rise in calcemia. Indeed, glucose intake induced a decrease in phosphatemia subsequent to the penetration of phosphate into cells as required for glucose phosphorylation (15). The acute diminution of serum phosphate might stimulate mineral bone release, causing, in turn, a rise in calcemia (16). However, the decrease in phosphatemia was substantially smaller after aspartame ingestion than after glucose and was unlikely to have been triggered by the entry of glucose into cells. The increase in calciuria after glucose ingestion has also been mainly ascribed to insulin (6). After aspartame ingestion, we observed no change in either glycemia or insulinemia. This is consistent with previous studies using a single dose of either 400 or 500 mg aspartame (17, 18, 19). Thus, insulin is unlikely to have played an important role in the augmentation of calciuria after aspartame ingestion. Another mechanism should therefore be invoked in the aspartame-induced rise in calciuria. An increase in calciuria has been reported after stimulated intestinal absorption of calcium by high protein content (20, 21). As aspartame was ingested in a fasting state after an overnight fast, such a mechanism is unlikely to have played a major role in our study. However, the hydrolization of aspartame into phenylalanine and aspartic acid in the gastrointestinal tract and the phosphate activation of these amino acids in cells might cause a decrease in phosphatemia, which is likely to trigger acute bone mineral release (16).
The decreased urinary excretion of phosphate after glucose load resulted from the clear fall in plasma phosphate concentration, reducing, in turn, the renal filtered load of phosphate (15). Conversely, after aspartame ingestion, the lack of a significant change in phosphaturia is likely to have reflected the lesser decrease in phosphatemia.
One theoretical consequence of our results is that a long term high carbohydrate diet might unbalance calcium phosphate homeostasis and then cause osteopenia. However, it is difficult to extend the results of our acute single load study to a situation of a continuous daily high carbohydrate diet. Therefore, the ingestion of large amounts of glucose (22) and, to a lesser extent, aspartame as a factor of osteopenia remains speculative.
Urinary excretion of oxalate increased slightly after glucose load as in previous studies (8, 23), but did not change after the ingestion of aspartame. This may be linked to the metabolism of glucose after its intestinal absorption. Indeed, the high rate of glucose reaching the liver after a 75-g glucose load may saturate several enzymes of the glycogen synthesis pathway so that the remaining glucose would then be converted into oxalic acid (24, 25). The lack of change in oxaluria after aspartame intake may be linked to the low amount of amino acids reaching the liver.
In conclusion, using aspartame in confectionery and sugar-free soft drinks is beneficial to prevent obesity, tooth decay, and postabsorptive hypoglycemia. However, in our study the ingestion of aspartame induced a significant increase in calciuria unrelated to any change in oxaluria. High carbohydrate diets have been considered by several researchers to be a calcium-oxalate stone risk factor. Although oxaluria did not change after aspartame intake, the increase in calciuria suggests that it is advisable to avoid long term ingestion of large amounts of aspartame in patients with a history of urolithiasis. It has also been reported that a high carbohydrate intake may have a deleterious bone effect induced by a negative calcium balance. If this hypothesis is confirmed, aspartame should also be avoided in patients at risk of osteopenia. Nevertheless, our acute study does not prove aspartame ingestion to have a predominant role in bone disease. Indeed, assessing this hypothesis would require long term studies.
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Acknowledgments |
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Received May 15, 1997.
Revised September 5, 1997.
Accepted September 15, 1997.
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References |
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). Results are expressed as the mean ±
SEM. *, P < 0.05; **,
P < 0.01; ***, P < 0.001
(vs. baseline values in each situation). 
,
P < 0.05; 
) or glucose
(