Download Issues and Opinions

Issues and Opinions
Metabolic Consequences of a High Dietary-Protein Intake in Adulthood:
Assessment of the Available Evidence
Cornelia C. Metges1 and Christian A. Barth
Department Biochemistry and Physiology of Nutrition, Deutsches Institut für Ernährungsforschung (German
Institute of Human Nutrition) (DIfE), 14558 Bergholz-Rehbrücke, Germany
In Western Europe and the United States, protein consumption amounts to about 1.5 to 2 times (Adolf et al. 1994)
the recommended intakes (WHO 1985), which is currently
considered to be harmless and, according to public opinion,
may be even beneficial. Usually relatively short-term experimental studies on the effects of high-protein intakes have been
performed, and so the consequences of longer-term or chronic
nutrient intake are difficult to judge. Epidemiologic evidence,
on the other hand, which aims to circumvent this difficulty,
can be flawed by various biases, confounding effects or even
limitations of the data which make it difficult to obtain clearcut cause-effect relationships (Taubes 1995).
It was stated (WHO 1985) that “there are no functional
indicators that can usefully be applied in experimental situations to detect protein inadequacy before clinically detectable
changes occur.” This statement is equally pertinent for the
determination of the tolerable upper intake level (TUL)2
particularly, if adequacy of protein intake in various physiological situations (i.e., maintenance, growth, pregnancy, lactation) is to be estimated. Moreover, no extensive body of data
exists covering the issue.
However, there are bits and pieces of information suggesting that there is no benefit from increasing the dietary-protein
intake far above the recommended intake level. Below we
summarize the relevant available literature and attempt, by
making prudent assumptions, to estimate a TUL which is
defined as the highest level of daily intake that is likely to pose
no risk of adverse health effects (Institute of Medicine, Food
and Nutrition Board 1999).
An increase of daily protein intake from 1.35 to 2.62
g 䡠 kg⫺1 for 1 mon in the habitual diet (170 kJ 䡠 kg⫺1 䡠 d⫺1)
while performing daily weight training did not affect either
strength or muscle mass (Lemon et al. 1992). Also the response of protein turnover to exercise (4 h at 40% VO2 max.)
was independent of dietary protein intake (0.9 or 2.5 g 䡠 kg⫺1
䡠 d⫺1) from isoenergetic diets (Carraro et al. 1990). Highprotein meals did not enhance the stimulation of myofibrillar
synthesis induced by resistance exercise in muscle of elderly
men and women (Welle and Thornton 1998). Daily physical
exercise of increasing intensity at neutral energy balance (constant protein intake 0.57 g 䡠 kg⫺1 䡠 d⫺1) maintained body
protein by an improvement of N utilization (Butterfield and
Calloway 1984). This suggests that physical activity has a
positive effect on N retention even at a low level of protein
intake, provided energy balance is achieved. Millward et al.
(1994) stated that, “training and energy intake depress protein
needs and habitual protein intake elevates protein needs.” In
conclusion, the literature provides no evidence that protein
nutriture and physical performance are improved by highprotein diets, the more so as Garlick et al. (1999) considered
that there are currently no methods sensitive enough to detect
whether high-protein intake results in a long-term increase in
functional lean tissue.
Effects of high dietary-protein intakes during adulthood
Although dietary percentage of energy from fat declined in
recent years, prevalence of obesity has continued to rise in the
United States (Willett 1998). In a study comparing fat intake
of normal weight, moderately and severely obese subjects,
there was a strong correlation of body mass index (BMI) with
fat consumption but also with protein intake (g 䡠 d⫺1) (Alfieri
et al. 1997). A positive correlation between BMI and protein
intake (in % total energy) is frequently reported; however, this
may be caused by underreporting of nonprotein energy intake
(Voss et al. 1998). On the other hand, in nonobese volunteers,
intake of low-fat foods which corresponds to an increase in
protein intake by 2 energy % reduced energy intake and body
weight (Weststrate et al. 1998). Nevertheless, it would be
worthwhile to investigate the relationship between proteinintake level and the development of obesity.
A short-term moderate increase of protein intake (from 50 to
82 g/d) in healthy male volunteers resulted in an increase of
insulin secretion as estimated by 24-h C-peptide excretion (Remer et al. 1996) (Table 1). Also an adequate (0.74 g 䡠 kg⫺1 䡠 d⫺1)
Protein intake, lean body mass and physical performance
One of the main questions is whether chronic intake of
high-protein diets may be of any value in promoting increased
lean body mass (Garlick et al. 1999). The answer to this
question is important not only for athletes and body builders
who tend to believe that a high-protein intake is crucial for
their physical performance (Linseisen et al. 1993) but for all
those conditions characterized by a decreasing lean body mass,
as seen in the elderly (Nair 1995) and various catabolic situations.
1
To whom correspondence should be addressed.
Abbreviations used: BMI, body mass index; CI, confidence interval; IL,
interleukin; NIDDM, noninsulin-dependent diabetes; TUL, tolerable upper intake
level.
2
0022-3166/00 $3.00 © 2000 American Society for Nutritional Sciences. J. Nutr. 130: 886 – 889, 2000.
Manuscript received 20 August 1999. Initial review completed 29 September 1999. Revision accepted 6 December 1999.
886
CONSEQUENCES OF HIGH DIETARY-PROTEIN INTAKE
887
TABLE 1
Undesirable metabolic effects of high dietary-protein intakes in adult humans: experimental and epidemiological evidence
Daily protein intake2
Subjects1
Controlled
na
na
na
na
na
na
na
na
Epidemiological
na
na
50–75 y
⬎9 y
20–79 y
70 y
35–59 y
A
B
C
1.6
1.7
2.4
2.4
2.5
2.8
2.8
2.9
0.65
0.84
⬎1.8
0.1
0.5
4th quartile
3rd tertile
Outcome/increased risk
Reference
insulin secretion a
renal net acid excretion a
oxalate, glycolate excretion a
calcium excretion a
insulin sensitivity s, hepatic glucose output a
bone resorption a
glomerular filtration rate a
plasma glutamine s
Remer et al. 1996
Remer and Manz 1994
Holmes et al. 1993
Trilok and Draper 1989
Linn et al. 1996
Kerstetter et al. 1999
Kerstetter et al. 1999
Matthews and Campbell 1992
glomerular filtration rate a
noncarbonic acid production a
microalbuminuria
diabetes
renal cell cancer (RR3 1.9)
prostate cancer (OR 13.5)
forearm fracture (RR 1.22)
Brändle et al. 1996
Frassetto et al. 1998
Hoogeveen et al. 1998
Wolever et al. 1997
Chow et al. 1994
Vlajinac et al. 1997
Feskanich et al. 1996
1 na, normal adults ⬍40 y, if not stated otherwise.
2 A ⫽ calculated as protein intake divided by the recommended dietary-protein intake of 0.75 g 䡠 kg⫺1 䡠 d⫺1 (WHO 1985). B ⫽ correlation between
protein intake and outcome. C ⫽ increase in protein intake (g 䡠 kg⫺1 䡠 d⫺1) above mean of study population.
3 RR, relative risk; OR, odds ratio.
compared to a high-protein intake (1.87 g 䡠 kg⫺1 䡠 d⫺1) was
associated with a higher overall insulin sensitivity and lower
hepatic glucose output (Linn et al. 1996). Interestingly, it was
suggested that amino acids are the most important source of
gluconeogenesis, and thus amino acid catabolism may have a
much greater effect on energy equilibrium than has been thought
previously (Jungas et al. 1992, Reeds et al. 1998). In a 50- to 75y-old Caucasian population, a daily increment of 0.1 g protein 䡠
kg⫺1 was associated with an increased risk for microalbuminuria,
which is a predictor of renal and cardiovascular disease
(Hoogeveen et al. 1998). A 1 SD-increase of protein intake
increased the risk of diabetes by 38% in an aboriginal community
in Canada (Wolever et al. 1997). That amino acids may contribute to insulin resistance was concluded from results of a recent
study in myotube cells (Patti et al. 1998).
A further indication that the high intake of protein may
have adverse effects can be taken from studies investigating
lifestyle changes (i.e., adopting Westernized dietary habits) in
Japanese men and schoolchildren. A higher incidence of noninsulin-dependent diabetes (NIDDM) correlated with increased animal protein and animal fat intakes while total
energy intake was not different from controls (Kitagawa et al.
1998, Tsunehara et al. 1990).
It has been reported that a chronic high-protein intake is
associated with a range of functional and morphological
changes such as increased urinary nitrogen excretion, vasopressin plasma levels, creatinine clearance, glomerular filtration rate, kidney hypertrophy, renal hemodynamics and eicosanoid production in renal tubules (Bankir and Kriz 1995,
Brändle et al. 1996, Yanagisawa and Wadi 1998). In addition,
increased risk of renal cell cancer has been linked to highprotein intake (Chow et al. 1994) (Table 1), while among
white males with indicators of kidney disease an increased
relative risk of total mortality with an additional 15 g of
protein per day [1.25; 95% confidence interval (CI) ⫽ 1.09,
1.42] was observed (Dwyer et al. 1994). Patients with moderate renal insufficiency benefit from a low-protein diet by slowing the deterioration of renal functions (Klahr et al. 1994,
Maroni and Mitch 1997). In addition, epidemiological evidence suggests a relationship between high-protein intake and
prostate cancer (Vlajinac et al. 1997) (Table 1).
Further, the risk of calcium oxalate stone formation has
been associated with the intake of protein, although this
relationship has not been found consistently (Curhan et al.
1993, Hiatt et al. 1996,Trinchieri et al. 1991). Oxalate is
generated from glycine (Elder and Wyngaarden 1960), but it
appears that variations in dietary oxalate as well as absorption
and excretion rates and generation of oxalate from breakdown
of ascorbic acid may disguise a relationship between protein
intake and calcium oxalate nephrolithiasis in epidemiological
studies. However, it was shown in a controlled nutritional
study that a high-protein diet (1.8 g 䡠 kg ⫺1 䡠 d⫺1) did lead to
higher oxalate excretion by female subjects and higher glycolate (precursor of oxalate) excretion in both sexes compared to
a low-protein diet (0.6 g 䡠 kg ⫺1 䡠 d⫺1) (Holmes et al. 1993).
An association between high-protein intake, renal acid and
calcium excretion has been reported (Ball and Maughan 1997,
Remer and Manz 1994,Trilok and Draper 1989). This may be
due to the oxidation of sulfur amino acids (methionine, cysteine), resulting in a decreased fractional renal tubular reabsorption of calcium (Houillier et al. 1996, Trilok and Draper
1989, Zemel 1988). Diets based mainly on plant proteins
apparently do not augment calcium loss, presumably because
of a higher phosphate intake and a lower intake of sulfur
amino acids (Ball and Maughan 1997, Zemel 1988). However,
in respect to protein quality, animal protein is superior to plant
protein, maintaining nitrogen balance and thus reducing protein intake. Dietary phosphate modifies the calciuretic effect
of proteins, because it increases renal tubular reabsorption of
calcium. The protein-induced calciuria has potential negative
effects on bone health (Barzel and Massey 1998, Feskanich et
al. 1996, Kerstetter et al. 1999) although this is controversial
(Heaney 1998, Munger et al. 1999).
A high-protein intake was found to result in a mild metabolic acidosis (Frassetto et al. 1998). Again, it appears that
sulfur (amino acid) content correlated with renal net acid
METGES AND BARTH
888
excretion (Frassetto et al. 1998). Chronic metabolic acidosis
decreases protein synthesis, increases protein breakdown and
may induce a negative nitrogen balance (Ballmer et al. 1995).
Recently a decrease in thyroid function in metabolic acidosis
was observed which might partly explain the effects on protein
turnover (Brungger et al. 1997). High- protein intake (⬎2
g 䡠 kg⫺1 䡠 d⫺1) is also accompanied by a decrease of plasma
levels of glutamine, alanine and glycine (Maher et al.
1984,Matthews and Campbell 1992). The decline in glutamine can also be a function of metabolic acidosis (Welbourne 1980), which increases renal glutamine extraction
(Welbourne et al. 1986) and decreases glutamine utilization by
lymphocytes (Wu and Flynn 1995). Glutamine homeostasis at
a high dietary-protein intake is maintained by a decreased de
novo production of glutamine (Matthews and Campbell 1992)
and an increase of hepatic glutaminase expression (Curthoys
and Watford 1995).
In catabolic patients, plasma glutamine concentration decreases (Jackson et al. 1999, Newsholme and Calder 1997).
Glutamine is an important fuel for the intestine and rapidly
dividing cells, such as lymphocytes (Newsholme and Calder
1997), and reduction in plasma glutamine was shown to be
linked to loss of CD4 ⫹ T cells in response to anaerobic
training (Hack et al. 1997). Decreased glutamine concentration impaired the ability of cultured lymphocytes to produce
interleukin (IL)-2 and to proliferate (Yaqoob and Calder
1997). Further, glutamine plays a role in the regulation of
gluconeogenesis (Perriello et al. 1997), in protein homeostasis
(Hankard et al. 1996) and in an experimental human model of
glutamine depletion, whole body protein synthesis decreased
(Darmaun et al. 1998). Low plasma glutamine levels due to a
high-protein intake may reduce immunologic competence and
impair body protein synthesis, particularly when subjects are
metabolically stressed.
Based on the foregoing, it is not evident that high-protein
intakes confer any advantage in terms of strength or health.
Moreover, high-protein intakes must be considered in relationship to the possible untoward consequences mentioned.
Due to the lack of systematic data, a specific TUL cannot yet
be set for a healthy adult population. However, it would be
prudent not to increase protein intakes above those consumed
habitually by well-nourished populations in the technically
advanced nations (2 g 䡠 kg⫺1 䡠 d⫺1). This is in accordance with
the recent recommendation by the International Dietary Energy Consultative Group (Durnin et al. 1999).
LITERATURE CITED
Adolf, T., Eberhardt, W., Heseker, H., Hartmann, S., Herwig, A., Matiaske, B.,
Moch, K. J., Schneider, R. & Kübler, W. (1994) Lebensmittel- und Nährstoffaufnahme in der Bundesrepublik Deutschland. Ergänzungsband zum
Ernährungsbericht 1992 (Food and nutrient intake in the Federal Republic of
Germany. Supplement to the Nutrition Report 1992), (Kübler, W., Anders, H. J.
& Heeschen, W., eds.), Vol. 12, VERA-Schriftenreihe, Wissenschaftlicher
Fachverlag Dr. Fleck, Niederkleen, Germany.
Alfieri, M., Pomerleau, J. & Grace, D. M. (1997) A comparison of fat intake of
normal weight, moderately obese and severely obese subjects. Obes. Surg. 7:
9 –15.
Ball, D. & Maughan, R. J. (1997) Blood and urine acid-base status of premenopausal omnivorous and vegetarian women. Br. J. Nutr. 78: 683– 693.
Ballmer, P. E., McNurlan, M. A., Hulter, H. N., Anderson, S. E., Garlick, P. J. &
Krapf, R. (1995) Chronic metabolic acidosis decreases albumin synthesis
and induces negative nitrogen balance in humans. J. Clin. Invest. 95: 39 – 45.
Bankir, L. & Kriz, W. (1995) Adaptation of the kidney to protein intake and to
urine concentrating activity: similar consequences in health and CRF. Kidney
Int. 47: 7–24.
Barzel, U. S. & Massey, L. K. (1998) Excess dietary protein can adversely affect
bone. J. Nutr. 128: 1051–1053.
Brändle, E., Sieberth, H. G. & Hautmann, R. E. (1996) Effect of chronic dietary
protein intake on the renal function in healthy subjects. Eur. J. Clin. Nutr. 50:
734 –740.
Brungger, M., Hulter, H. N. & Krapf, R. (1997) Effect of chronic metabolic
acidosis on thyroid hormone homeostasis in humans. Am. J. Physiol. 272:
F648 –F653.
Butterfield, G. E. & Calloway, D. H. (1984) Physical activity improves protein
utilization in young men. Br. J. Nutr. 51: 171–184.
Carraro, F., Hartl, W. H, Stuart, C. A., Layman, D. K., Jahoor, F. & Wolfe, R. R.
(1990) Whole body and plasma protein synthesis in exercise and recovery in
human subjects. Am. J. Physiol. 258: E821–E831.
Chow, W. H., Gridley, G., McLaughlin, J. K., Mandel, J. S., Wacholder, S., Blot,
W. J., Niwa, S. & Fraumeni, J. F. Jr. (1994) Protein intake and risk of renal
cell cancer. J. Natl. Cancer Inst. 86: 1131–1139. .
Curhan, G. C., Willett, W. C., Rimm, E. B. & Stampfer, M. J. (1993) A prospective study of dietary calcium and other nutrients and the risk of symptomatic
kidney stones. N. Engl. J. Med 328: 833– 838.
Curthoys, N. P. & Watford, M. (1995) Regulation of glutaminase activity and
glutamine metabolism. Annu. Rev. Nutr. 15: 133–159.
Darmaun, D., Welch, S., Rini, A., Sager, B. K., Altomare, A. & Haymond, M. W.
(1998) Phenylbutyrate-induced glutamine depletion in humans: effect on
leucine metabolism. Am. J. Physiol. 274: E801–E807.
Durnin, J. V., Garlick, P., Jackson, A. A., Schurch, B. & Shetty, P. S. & Waterlow,
J. C. (1999) Report of the IDECG Working Group on lower limits of energy
and protein and upper limits of protein intakes. International Dietary Energy
Consultative Group. Eur. J. Clin. Nutr. 53 Suppl 1: S174 –S176.
Dwyer, J. T., Madans, J. H., Turnbull, B., Cornoni-Huntley, J., Dresser, C., Everett,
D. F. & Perrone, R. D. (1994) Diet, indicators of kidney disease, and later
mortality among older persons in the NHANES I epidemiologic follow-up
study. Am. J. Pub. Health. 84: 1299 –1303.
Elder, T. D. & Wyngaarden, J. B. (1960) The biosynthesis and turnover of
oxalate in normal and hyperoxaluric subjects. J. Clin. Invest. 39: 1337–1344.
Feskanich, D., Willett, W. C., Stampfer, M. J. & Colditz, G. A. (1996) Protein
consumption and bone fractures in women. Am. J. Epidemiol. 143: 472– 479.
Frassetto, L. A., Todd, K. M., Morris, R. C. Jr. & Sebastian, A. (1998) Estimation
of net endogenous noncarbonic acid production in humans from diet potassium and protein contents. Am. J. Clin. Nutr. 68: 576 –583.
Garlick, P. J., McNurlan, M. A. & Patlak, C. S. (1999) Adaptation of protein
metabolism in relation to limits to high dietary protein intake. Eur. J. Clin. Nutr.
53 Suppl 1: S34-S43.
Hack, V., Weiss, C., Friedmann, B., Suttner, S., Schykowski, M., Erbe, N., Benner,
A., Bartsch, P. & Droge, W. (1997) Decreased plasma glutamine level and
CD4⫹ T cell number in response to 8 wk of anaerobic training. Am. J. Physiol.
272: E788-E795.
Hankard, R, G., Haymond, M. W. & Darmaun, D. (1996) Effect of glutamine on
leucine metabolism in humans. Am. J. Physiol. 271: E748-E754.
Heaney, R. P. (1998) Excess dietary protein may not adversely affect bone. J.
Nutr. 128: 1054 –1057.
Hiatt, R. A., Ettinger, B., Caan, B., Quesenberry, C. P., Duncan, D. & Citron, J. T.
(1996) Randomized controlled trial of a low animal protein, high-fiber diet in
the prevention of recurrent calcium oxalate kidney stones. Am. J. Epidemiol.
144: 25–33.
Holmes, R. P., Goodman, H. O., Hart, L. J. & Assimos, D. G. (1993) Relationship of protein intake to urinary oxalate and glycolate excretion. Kidney Int.
44: 366 –372.
Hoogeveen, E. K., Kostense, P. J., Jager, A., Heine, R. J., Jakobs, C., Bouter,
L. M., Donker, A. J. & Stehouwer, C. D. (1998) Serum homocysteine level
and protein intake are related to risk of microalbinuria: the Hoorn study.
Kidney Int. 54: 203–209.
Houillier, P., Normand, M., Froissart, M., Blanchard, A., Jungers, P. & Paillard, M.
(1996) Calciuric response to an acute acid load in healthy subjects and
hypercalciuric calcium stone formers. Kidney Int. 50: 987–997.
Institute of Medicine, Food and Nutrition Board. (1999) http://www2.nas.edu/
Fnb/216a.html.
Jackson, N. C., Carroll, P. V., Russell-Jones, D. L., Sonksen, P. H., Treacher, D. F.
& Umpleby A. M. (1999) The metabolic consequences of critical illness:
acute effects on glutamine and protein metabolism. Am. J. Physiol. 276:
E163-E170.
Jungas, R. L., Halperin, M. L. & Brosnan, J. T. (1992) Quantitative analysis of
amino acid oxidation and related gluconeogenesis in humans. Physiol. Rev.
72: 419 – 448.
Kerstetter, J. E., Mitnick, M. E., Gundberg, C. M., Caseria, D. M., Ellison, A. F.,
Carpenter, T. O. & Insogna, K. L. J. (1999) Changes in bone turnover in
young women consuming different levels of dietary protein. J. Clin. Endocrinol. Metab. 84: 1052–1055.
Kitagawa, T., Owada, M., Urakami, T. & Yamauchi, K. (1998) Increased incidence of non-insulin dependent diabetes mellitus among Japanese schoolchildren correlates with an increased intake of animal protein and fat. Clin.
Pediatr. (Phila) 37: 111–115.
Klahr, S., Levey, A. S., Beck, G. J., Caggiula, A. W., Hunsicker, L., Kusek, J. W.
& Striker, G. (1994) The effects of dietary protein restriciton and bloodpressure control on the progression of chronic renal disease. N. Eng. J. Med.
330: 877– 884.
Lemon, P. W. R., Tarnopolsky, M. A., Mac Dougall, J. D. & Atkinson, S. A. (1992)
Protein requirements and muscle mass/strength changes during intensive
training in novice bodybuilders. J. Appl. Physiol. 73: 767–775.
Linn, T., Geyer, R., Prassek, S. & Laube, H. (1996) Effect of dietary protein
intake on insulin secretion and glucose metabolism in insulin-dependent
diabetes mellitus. J. Clin. Endocrinol. Metab. 81: 3938 –3953.
CONSEQUENCES OF HIGH DIETARY-PROTEIN INTAKE
Linseisen, J., Metges, C. C. & Wolfram, G. (1993) Dietary habits and serum
lipids of a group of German amateur body-builders. Z. Ernährungswiss. 32:
289 –300.
Maher, T. J., Glaeser, B. S. & Wurtman, R. J. (1984) Diurnal variations in
plasma concentrations of basic and neutral amino acids and in red cell
concentrations of aspartate and glutamate: effects of dietary protein intake.
Am. J. Clin. Nutr. 39: 722–729.
Maroni, B. J. & Mitch, W. E. (1997) Role of nutrition in prevention of the
progression of renal disease. Annu. Rev. Nutr. 17: 435– 455.
Matthews, D. E. & Campbell, R. G. (1992) The effect of dietary protein intake
on glutamine and glutamate nitrogen metabolism in humans. Am. J. Clin.
Nutr. 55: 963–970.
Millward, J., Bowtell, J. L., Pacy, P. & Rennie, M. J. (1994) Physical activity,
protein metabolism and protein requirements. Proc. Nutr. Soc. 53: 223–240.
Munger, R. G., Cerhan, J. R. & Chiu, B. C. (1999) Prospective study of dietary
protein intake and risk of hip fracture in postmenopausal women. Am. J. Clin.
Nutr. 69: 147–152.
Nair, K. S. (1995) Muscle protein turnover: methodological issues and the
effect of aging. J. Gerontol. A Biol. Sci. Med. Sci. 50 Spec No: 107–112.
Newsholme, E. A. & Calder, P. C. (1997) The proposed role of glutamine in
some cells of the immune system and speculative consequences for the
whole animal. Nutrition 13: 728 –730.
Patti, M.-E., Brambilla, E., Luzi, L., Landaker, E. J. & Kahn, C. R. (1998)
Bidirectional modulation of insulin action by amino acids. J. Clin. Invest. 101:
1519 –1529.
Perriello, G., Nurjhan, N., Stumvoll, M., Bucci, A., Welle, S., Dailey, G., Bier, D. M.,
Toft, I., Jenssen, T. G. & Gerich, J. E. (1997) Regulation of gluconeogenesis by glutamine in normal postabsorptive humans. Am. J. Physiol. 272 (3 Pt
1): E437– 445.
Reeds, P. J., Burrin, D. G., Davis, T. A. & Stoll, B. (1998) Amino acid metabolism and the energetics of growth. Arch. Anim. Nutr. 51: 187–197.
Remer, T. & Manz, F. (1994) Estimation of the renal net acid excretion by adults
consuming diets containing variable amounts of protein. Am. J. Clin. Nutr. 59:
1356 –1361.
Remer, T., Pietrzik, K. & Manz, F. (1996) A moderate increase in daily protein
intake causing an enhanced endogenous insulin secretion does not alter
circulating levels or urinary excretion of dehydroepiandrosterone sulfate. Metabolism 45: 1483–1486.
Taubes, G. (1995) Epidemiology faces its limits. Science 269: 164 –169.
Trilok, G. & Draper, H. H. (1989) Sources of protein-induced endogenous acid
production and excretion by human adults. Calcif. Tissue Int. 44: 335–338.
Trinchieri, A., Mandressi, A., Luongo, P., Longo, G. & Pisani, E. (1991) The
889
influence of diet on urinary risk factors for stones in healthy subjects and
idiopathic renal calcium stone formers. Br. J. Urology 67: 230 –236.
Tsunehara, C. H., Leonetti, D. L. & Fujimoto, W. Y. (1990) Diet of secondgeneration Japanese-American mean with and without non-insulin-dependent diabetes. Am. J. Clin. Nutr. 52: 731–738.
Vlajinac, H. D., Marinkovic, J. M., Ilic, M. D. & Kocev, N. I. (1997) Diet and
prostate cancer: a case-control study. Eur. J. Cancer 33: 101–107.
Voss, S., Kroke, A., Klipstein-Grobusch, K. & Boeing, H. (1998) Is macronutrient composition of dietary intake data affected by underreporting? Results
from the EPIC-Potsdam Study. European Prospective Investigation into Cancer and Nutrition. Eur. J. Clin. Nutr. 52: 119 –126.
Welbourne, T. C. (1980) Acid-base balance and plasma glutamine concentration in man. Eur. J. Appl. Physiol. 45: 185–188.
Welbourne, T. C., Phromphetcharat, V., Givens, G. & Joshi, S. (1986) Regulation of interorganal glutamine flow in metabolic acidosis. Am. J. Physiol.
250: E457-E463.
Welle, S. & Thornton, C. A. (1998) High-protein meals do not enhance myofibrillar synthesis after resistance exercise in 62- to 75-y-old men and women.
Am. J. Physiol. 271: E677-E683.
Weststrate, J. A., van het Hof, K. H., van den Berg, H., Velthuis-te-Wierik, E. J. M.,
de Graaf, C., Zimmermanns, N. J. H., Westerterp, K. R., Westerterp-Plantenga, M. S. & Verboeket-van de Venne, W. P. H. G. (1998) A comparison
of the effect of free access to reduced fat products or their full-fat equivalents
on food intake, body weight, blood lipids and fat-soluble antioxidants levels
and haemostasis variables. Eur. J. Clin. Nutr. 52: 389 –395.
WHO. Energy and protein requirements. Report of a joint FAO/WHO/UNU Expert
Consultation (1985) Technical Report No. 724. WHO, Geneva, Switzerland.
Willett, W. C. (1998) Is dietary fat a major determinant of body fat? Am. J. Clin.
Nutr 67(suppl): 556S-562S.
Wolever, T. M., Hamad, S., Gittelsohn, J., Gao, J., Hanley, A. J., Harris, S. B. &
Zinman, B. (1997) Low dietary fiber and high protein intakes associated
with newly diagnosed diabetes in a remote aboriginal community. Am. J. Clin.
Nutr. 66: 1470 –1474.
Wu, G. & Flynn, N. E. (1995) Effect of HCO3- on glutamine and glucose
metabolism in lymphocytes. Metabolism 44: 1247–1252.
Yanagisawa, H. & Wada, O. (1998) Effects of dietary protein on eicosanoid
production in rat renal tubules. Nephron 78: 179 –186.
Yaqoob, P. & Calder, P. C. (1997) Glutamine requirement of proliferating T
lymphocytes. Nutrition 13: 646 – 651.
Zemel, M. B. (1988) Calcium utilization: effect of varying level and source of
dietary protein. Am. J. Clin. Nutr. 48 (3 Suppl): 880 – 883.