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The Interaction Between Dietary Fructose and Magnesium Adversely Affects Macromineral Homeostasis in Men

United States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota 58202

Address reprint requests to: Forrest H. Nielsen, PhD, USDA/ARS, GFHNRC, PO Box 9034, Grand Forks, ND 58202-9034

	ABSTRACT

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Objective: Studies with rats have found that an interaction between fructose and magnesium affects macromineral metabolism; high dietary fructose significantly increased kidney calcification in both male and female rats, particularly when dietary magnesium was low. This study tests the hypothesis that an interaction between dietary fructose and magnesium adversely affects macromineral homeostasis in men.

Methods: Eleven men aged 22 to 40 years were fed a mixed, Western diet for four 42-day dietary periods in which dietary magnesium was either approximately 170 or 370 mg/day and dietary fructose was either 4% or 20% of energy. A decaffeinated beverage containing high fructose corn syrup replaced cornstarch, bread and rice in the low fructose diet to give the high fructose diet.

Results: High dietary fructose significantly (p<0.01) increased magnesium balance during both low and high dietary magnesium intakes. Ultrafilterable and ionized serum magnesium also apparently were related to magnesium and fructose intakes; they were higher when fructose was fed and when Mg intakes were high. High fructose depressed calcium balance: the effect tended to be more marked when dietary Mg was low. High dietary fructose also significantly (p<0.005) decreased phosphorous balance. Urinary phosphorous losses were significantly (p<0.001) higher when high dietary fructose was fed. High dietary fructose also increased the concentration of serum alkaline phosphatase (p<0.005).

Conclusion: These findings indicate that dietary fructose adversely affects macromineral homeostasis in humans and suggest further studies to see if a high fructose diet coupled with low dietary magnesium and marginal calcium leads to bone loss.

Key words: magnesium balance, calcium metabolism, calcium balance, phosphorous balance

	INTRODUCTION

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Refined sugar use has declined over the last 20 years, whereas high-fructose corn sweetener consumption has increased by more than 700% [1]. The ingestion of fructose at about 20% of dietary energy has been implicated in the induction of detrimental changes in indices associated with ischemic heart disease, gout and urolithiasis, when compared with starch. At least two studies [2,3] with both men and women demonstrated increases in total triglycerides, total cholesterol, LDL cholesterol and uric acid when high amounts of fructose were fed. Fructose also increased fasting serum glucose and increased urinary oxalate excretion.

Studies with animals have also demonstrated that dietary fructose at 20% of energy, when compared with starch, exacerbated signs of both copper and magnesium deficiencies [4,5]. Several studies document the induction of nephrocalcinosis in rats fed diets deficient in magnesium and high in sucrose [6,7]. Recently, a synergistic interaction between high dietary fructose and magnesium deficiency on kidney calcification was found [5]. Koh and Min [8] compared the interaction in male and female rats. High dietary fructose significantly increased kidney calcium in female rats fed deficient or adequate magnesium diets and in male rats fed the magnesium deficient diet only. The greatest kidney calcification occurred in female rats fed the high fructose and magnesium deficient diet. Fructose feeding also increased plasma calcium and magnesium.

Dietary surveys made since 1965 [9,10] indicate that self-selected diets provide marginal or suboptimal magnesium intakes, based on the recommended dietary allowances (RDA), for a significant percentage of adults. Because high dietary fructose consumption concomitant with magnesium intakes less than the recommended dietary allowance is likely a common occurrence, particularly in individuals consuming large amounts of soft drinks and eating few green vegetables, and because fructose and magnesium act synergistically to affect variables they independently adversely affect in rats, we designed the following study to test the hypothesis that an interaction between dietary fructose and magnesium adversely affects macromineral homeostasis in men.

	METHODS

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Healthy men aged 22 to 40 years were admitted to the study after they had been informed in detail of the nature of the research and associated risks and after medical, psychological and nutritional evaluations had established that they had no underlying disease and that they were emotionally suited for the project. Protocols were approved by the Institutional Review Boards of the University of North Dakota and the United States Department of Agriculture and followed the guidelines of the Department of Health and Human Services and the Helsinki doctrine regarding the use of human subjects.

The men were maintained in a metabolic unit under close supervision for approximately six months and fed a constant, weighed diet (Tables 1a and 1b), on a three-day menu rotation, that was low in magnesium (170 mg Mg/2500 kcal, by analysis). The diet was adequate in all other nutrients. After a 16-day equilibration period with starch at 20% of energy in a diet supplemented with 205 mg of magnesium per day, the study was divided into four 42-day dietary periods in a randomized, double-blind, 2 x 2 factorial design. Magnesium was varied at 170 and 370 mg/2500 kcal and starch and fructose at 20% of energy. Magnesium was supplemented as magnesium gluconate. Fructose was supplied mainly as high fructose corn sweetener in commercial sodas (Table 1a). The dietary intake of each subject was based on energy needs, as calculated by the Harris and Benedict equation [11], plus an additional 50% of basal energy expenditure for normal activity. During the study, energy intakes were adjusted to maintain the body weight to within ± 2% of admission weight by adjusting the amount of the basal diet in 200 kcal increments.

Magnesium, calcium and phosphorus were determined in aliquots of six-day composites of diets and feces. They were measured by inductively coupled argon plasma emission spectroscopy (ICAP) (Thermal ARL-VG Elemental, Div. of Thermal Jarell Ash Corp., Franklin, MA 02038) [12] after wet digestion of aliquots of freeze-dried, blended material with nitric and perchloric acids [13]. Urinary magnesium, calcium and phosphorus were determined by ICAP analysis of a diluted aliquot. Concurrent replicate analysis of a Total Diet SRM #1548 (n=8) (National Institute of Standards and Technology, Gaithersburg, MD 20899) yielded values of 1675 ±23, 531 ±4, and 3240 ±84 µg/g as compared with certified values of 1740 ±70, 556 ±27, and 3240 ±40 µg/g for Ca, Mg and P, respectively. A fecal pool analyzed concurrently (n=14) yielded values of 40.1 ±1.3, 13.1 ±0.5, and 24.6 ±1.3 mg/g as compared with expected ranges of 35.0 to 45.0, 10.1 to 13.2, and 23.0 to 28.0 mg/g for Ca, Mg, and P, respectively.

Blood was drawn into plastic syringes from an anticubal vein, which had been made visible by temporary use of a tourniquet, after the subjects had fasted for 10 hours. Aliquots were mixed with appropriate anticoagulants and processed within 90 minutes of the time the blood was drawn. Serum magnesium and calcium concentrations were determined by flame atomic absorption spectrophotometry after dilution 50-fold with an acidic lanthanum chloride diluent [14]. Ionized calcium and magnesium were determined by using a NOVA CRT 8+ electrolyte analyzer (Nova Biomedical, Waltham, NJ 02254). Serum ultrafiltrates were prepared by using an Amicon MPS-1 filter system (Amicon, Inc., Beverly, MA 01915) and a procedure described by D’Costa and Cheng [15]. The magnesium content of the ultrafiltrate was determined by ICAP analysis [12]. Serum phosphate was determined by a modification of an automated procedure described by Daly et al. [16]. Parathyroid hormone (PTH) and osteocalcin were determined by using commercially available radioimmunoassay kits (Incstar, Stillwater, MN 55082).

Data were analyzed by repeated measures analysis of variance [17]. Differences with p values 0.05 were considered significant.

	RESULTS

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Magnesium balance was independently affected by both magnesium and fructose intakes in the eleven men who completed the study (Table 2). Magnesium balance and fecal and urinary magnesium were all directly related to magnesium intake. Substituting high fructose for starch resulted in higher magnesium balance at both low and high magnesium intake. Urinary excretion of magnesium was unaffected by elevated dietary fructose, but fecal excretion was decreased at both levels of magnesium intake. This indicated increased absorption and retention of magnesium during periods of higher fructose intake. The men were in negative magnesium balance when fed the starch diet containing 165 mg magnesium per day.

	DISCUSSION

The findings from this study support the hypothesis that high dietary fructose affects macromineral homeostasis in humans. The increase in magnesium balance when fructose was fed is consistent with observations by Holbrook et al. [19], who found increased absorption and retention of magnesium and other minerals when fructose was fed as compared with starch. However, in the same study the authors also reported a more positive balance for calcium when fructose was fed as opposed to starch, contrary to what was seen in this study. A likely difference could be that in the study of Holbrook et al. [19], calcium intakes were much lower when starch was fed and higher when high dietary fructose was fed. Our results for calcium were more consistent with those of Hallfrisch et al. [20], who found decreased calcium balance when simple sugars were fed compared with complex carbohydrates, and Ivaturi and Kies [21] who reported lower calcium balance when fructose was fed than when sucrose was fed.

The mechanisms by which fructose affects magnesium absorption and balance are largely unknown. It has been hypothesized that fructose may form complexes with mineral elements, such as magnesium, in the gut and these complexes may facilitate mineral absorption. Fructose is readily absorbed by man and rats without conversion to other sugars via facilitated diffusion [22]. Thus a magnesium-fructose complex may be more readily absorbed. This hypothesis is consistent with observations of Van Der Heijden et al. [23], who suggested that fructose enhanced the ileal solubility of magnesium, which in turn elevates the amount of magnesium that can cross the epithelium. The possibility that, in the intestine, fructose can form a stable, soluble chelate with magnesium has been demonstrated under in vitro conditions by Charley et al. [24].

Although the high fructose diet contained slightly less calcium and slightly more phosphorus than the starch diet, it is unlikely that the small change in the Ca/P ratio contributed to a lower calcium balance. Spencer et al. [25] demonstrated that high phosphorus intakes did not interfere with calcium absorption over a ten-fold range of calcium intakes. This supported the view of some investigators [26,27] and the World Health Organization [28] that the dietary Ca/P ratio in humans does not play an important role in terms of the utilization and retention of calcium. However, in these studies, a decrease in urinary calcium was reported with increased phosphorus intake [20]. In this study, urinary losses of calcium as a percent of calcium intake were significantly (p<0.01) higher during the high fructose intake (and higher phosphorus intake) periods than during the starch dietary periods.

The increased urinary excretion of phosphorus and negative phosphorus balance when high dietary fructose was fed are consistent with studies of Bergstra et al. [29], who found that dietary fructose induced greater urinary concentrations of phosphorus and lowered urinary pH in female rats when compared with glucose. They suggested that the increased urinary excretion of phosphorus was the result of increased absorption from the diet. In this study there was an apparent increase in the absorption of phosphorus from the diet (100 percent of dietary phosphorus in feces). However, more phosphorus was lost in the urine than could be accounted for by both increased dietary intake and increased absorption.

Although plasma phosphate and PTH were unaffected by dietary treatment in this study, the large negative phosphorus balance during the high fructose, low magnesium dietary period may be of some concern. It is likely that longer periods of negative phosphorus balance could lead to a phosphate deficiency and hypophosphatemia. Hypophosphatemia has been observed in patients receiving parenteral nutrition or after infusions of fructose [30]. It was suggested that the hypophosphatemia found after fructose administration was the result of unregulated uptake of fructose by the liver and consequent formation of fructose-1-phosphate [31] and increased phosphate turnover. Some long-term consequences of hypophosphatemia include muscular weakness, cardiomyopathy, bone pain and osteomalacia or rickets [30,32].

The lower retention of calcium and greater losses of phosphorus when large amounts of fructose were fed, particularly in combination with a magnesium low diet, suggests an adverse impact on bone health if the trend continued over a longer period of time. This is consistent with findings of Nguyen et al. [33], who found increased urinary calcium losses after fructose infusion, and those of Guthmann et al. [34], who demonstrated a stimulation of bone calcium release by carbohydrate. These observations may be of concern from a public health standpoint since the intake of magnesium has decreased appreciably since the beginning of this century [9,10], while fructose consumption has been increasing rapidly since the introduction of high fructose corn syrup in 1970 [1]. This trend seems to be the most dramatic in children in the US, who are consuming large amounts of soft drinks containing high fructose corn syrup [35] at the expense of foods containing adequate amounts of magnesium and calcium. Thus, additional studies are indicated to determine if a high fructose containing diet combined with low dietary magnesium and marginal calcium leads to bone loss.

	ACKNOWLEDGMENTS

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We thank the members of the Grand Forks Human Nutrition Research Center clinical staff whose special talents and skills made this study possible: LM Klevay (medical supervision), HC Lukaski (exercise physiology), B Vetter (nursing care), B Hoverson and staff (dietary), L Johnson (statistical analysis), and S Gallagher and the Analytical Biochemistry Laboratory staff (clinical chemistry).

	FOOTNOTES

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The U.S. Department of Agriculture, Agricultural Research Service, Northern Plains Area, is an equal opportunity/affirmative action employer and all agency services are available without discrimination. Mention of a trademark or proprietary product does not constitute a guarantee or warranty of the product by the United States Department of Agriculture and does not imply its approval to the exclusion of other products that may also be suitable.

Received September 1, 1999. Revised November 1, 1999.

	REFERENCES

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