DIETARY PROTEIN: HEALTH AND WELL BEING
Establishing Cause and Effect between Diet and Disease
One of the challenges faced by nutritional scientists when they ultimately make recommendations regarding what we should and should not eat is to establish cause and effect between a dietary element and the subsequent development or prevention of disease. Some foods and some dietary habits promote good health whereas others promote disease.
No single procedure alone can establish cause and effect,65, 66 nor can any single study prove causality.67 Observational epidemiological studies can only show relationships among variables and are notorious for showing conflicting results68 and cannot provide decisive evidence by themselves either for or against specific hypotheses.69 For example increased animal protein has been associated with a decreased risk for coronary heart disease (CHD) in a large group of nurses (The Nurses Health Study),70 whereas exactly the opposite association was found for markers of CHD and meat consumption in people from rural China.71, 72 An analogy here may be appropriate to show you why observational epidemiological studies can only show relationships and not establish causality. In New York City, there is a strong association between the size of a structure fire and the number of fire trucks at the fire, but can we conclude that more fire trucks cause bigger fires?
In order to establish cause and effect between diet and disease, it takes more than just observational epidemiological evidence.69 There must also be what is referred to as “biological plausibility” in which evidence gathered from tissue, animal and short term human metabolic studies support causality.66 When observational epidemiological evidence is augmented by biological plausibility studies and confirmed by randomized controlled trials, the case for causality becomes ever more convincing. In regard to optimal amounts of dietary protein, the bulk of the evidence from tissue and animal studies and from human dietary interventions provides a compelling case for the therapeutic effects of high protein diets.
Dietary Protein and Cardiovascular Disease
One of the reasons why observational epidemiological studies yield contradictory results is because of the influence of confounding variables which cause confusion in the interpretation of the results because of the mixing of effects from two or more variables.68 For example, although some observational studies have shown a positive association between animal protein and cardiovascular disease (CVD), it is entirely possible that this association is spurious because the measurement of animal protein is confounded by another variable that is also linked to CVD. Meat is a major source of animal protein in the U.S. diet,20 but it is also a major source of saturated fat.73 Because meat comes as an inseparable package of (protein + saturated fat), animal protein ingestion will be highly correlated to saturated fat, thereby making it difficult to disengage the atherogenic effect of saturated fat from that of animal protein. Accordingly, experimental studies are more useful to determine the true effect animal protein may have upon cardiovascular risk factors because they can be designed to isolate the protein effects from the saturated fat effects.
Sinclair and colleagues74 performed an experiment in which they fed 10 adults a low fat, lean beef-based diet for five weeks. Energy intake was kept constant over the five week study. Total blood cholesterol concentrations fell significantly within one week of commencing the diet, but rose as beef fat drippings were added in a stepwise manner in weeks four and five. The authors concluded, “. . . it is the beef fat, not lean beef itself, that is associated with elevations in cholesterol concentrations.”
Numerous short term human dietary interventions have demonstrated the therapeutic effect of lean, animal based protein upon blood lipid parameters. Wolfe and colleagues have shown that the isocaloric substitution of protein (23% energy) for carbohydrate in moderately hypercholesterolemic subjects resulted in significant decreases in total, LDL and VLDL cholesterol, and triglycerides while HDL cholesterol increased.75 Similar blood lipid changes have been observed in normal healthy subjects76 and in type II diabetic patients in conjunction with improvements in glucose and insulin metabolism.77, 78
A litany of more recent studies has confirmed that elevations in dietary protein have a beneficial effect upon blood lipid profiles.79-85 The mechanism or mechanisms of action of high protein diets upon blood lipid chemistry are not clear; however animal studies suggest that the beneficial effects are caused by their powerful inhibition of hepatic VLDL synthesis, perhaps by altering apoprotein synthesis and assembly in the liver.86
The relationship between protein intake and blood pressure has been comprehensively examined in observational population studies, and support the notion that higher protein intake can lower blood pressure.87-89 A substantial number of randomized controlled trials have demonstrated that higher dietary protein either from soy,90-92 mixed dietary sources85 or from lean red meat93 significantly lower blood pressure.
Dietary Protein and Insulin/Glucose Metabolism and Weight Regulation
In addition to reducing CVD risk by improving the blood lipid profile and reducing blood pressure, higher protein diets have been shown to improve insulin sensitivity and glycemic control79, 81, 84, 94-96 while promoting greater weight loss80, 83, 84, 97, 98 and improved long term sustained weight maintenance99, 100 than low fat high carbohydrate calorie restricted diets. The weight loss superiority of higher protein, calorie restricted diets over either calorie restricted (low fat/ high carbohydrate) diets or calorie restricted (high fat/low carbohydrate) appears to be caused by the greater satiety value of protein compared to either fat or carbohydrate.macronutrients (protein, fat, carbohydrate), protein causes the greatest release of a gut hormone (PYY) that reduces hunger103 while simultaneously improving central nervous system sensitivity to leptin,97 another hormone that controls appetite and body weight regulation.
Dietary Protein and Bone Health
One of the crucial issues regulating bone mineral health and integrity is calcium balance which represents the difference between the amount of dietary calcium which is absorbed and the amount of calcium leaving the body through the urine and feces. Figure 5 demonstrates two key points: 1) most (~75%) of dietary calcium is not absorbed, and 2) calcium absorption increases with decreasing dietary intakes and decreases with increasing dietary intakes.104
Because dietary protein has been frequently, but not always,105-108 shown to increase urinary calcium excretion, it is possible that long term ingestion of high protein diets could lead to accelerated loss of calcium from the bones thereby impairing bone health and integrity.
Without the concurrent measurement of dietary calcium absorption along with urinary calcium losses the net calcium balance cannot be known. Hence, the simple observation that dietary protein ingestion may increase urinary calcium losses tells us little or nothing about calcium balance. In evaluating the effect of high protein diets upon bone mineral health, it is therefore crucial to measure both urinary calcium excretion and intestinal absorption of calcium. In this regard, Pannemans and colleagues109 compared a low protein (12% energy) to a high protein diet (21% energy) in young and elderly subjects. Both a higher urinary calcium excretion and a higher intestinal absorption of calcium were induced by the high protein diet, thus no negative calcium balance occurred.
A similar experiment confirmed that elevated dietary protein enhances calcium absorption and thereby counters the increased urinary excretion of calcium.110
Furthermore, a series of recent dietary interventions in humans has shown that high protein, meat based diets do not cause loss of calcium from the skeleton, but actually have a favorable effect upon it by lowering bone resorption105, 107, 111, 112 and may actually increase bone formation by dietary protein induced increases in IFG-1.105
Dietary Protein and Kidney Function
One of the most common misperceptions about high protein diets is that they can damage the kidneys of healthy normal individuals. This concept is known as the “Brenner Hypothesis”113 and suggests that increased dietary protein elevates the kidney’s filtration rate (GFR) which in turn alters the kidney’s structure (glomerulosclerosis) which then causes albumin to appear in the urine (microalbuminuria). Although these series of steps represent the hypothesis Brenner proffered,113 his experiments actually showed an entirely different series of events. In reality, Brenner demonstrated that patients with pre-existing kidney disease had an elevated GFR, glomerulosclerosis and microalbuminuria and that by reducing dietary protein the GFR and microalbuminuria could be lowered.113 He further suggested that because elevated dietary protein increased the GFR in short term studies (< 2 weeks) of healthy normal subjects, protein was responsible for kidney damage. The problem with this interpretation is that markers of functional kidney damage in the normal subjects (microalbuminuria) were not demonstrated along with the elevations in GFR, nor were any long term studies (3-6 months) carried out to determine if the kidneys adapted to a higher protein intake.
The incidence of diabetic end stage kidney disease has increased steadily over the past three decades.114, 115 If dietary protein were responsible for causing kidney damage, then one might expect that dietary protein would have steadily increased during this same time interval. In fact, dietary proten significand female subjects.118 The high protein diet did not cause urinary albumin to increase. Additionally, the specific GFR, which is an expression of the filtration rate per unit kidney volume, did not change during the high protein diet, indicating that renal (kidney) adaptation occurred to the higher protein load. The authors summarized, “We therefore conclude that a high dietary protein intake does not appear to have adverse effects on renal function in individuals without renal impairment.”
Dietary Protein and Cancer
Observational epidemiological studies frequently,119 but not always120 show that high animal protein diets may increase the risk for a variety of cancers, particularly colorectal cancer.121 Consequently, it might be expected that non-meat eating vegetarians would have a lower risk for these cancers. Paradoxically, this effect has not been consistently demonstrated.119 A proposed mechanism of action for the carcinogenic effect of meat consumption is the formation of toxic N-nitroso compounds (NOC) in the gut from heme iron in meat.122, 123 Short term human studies are in agreement that increased meat consumption increases NOC formation both in the lower122 and upper123 gastrointestinal tract. However, whether this situation translates into increased cancer risk is not known because to date, no randomized controlled trials of increased meat consumption in humans, using cancer diagnosis as an end point, have been conducted.
The meats and fish consumed by pre-agricultural humans were almost always fresh, whereas current western diets contain significant quantities of processed, salted meats and fish preserved with nitrites and nitrates. Processed meats contains 10 times more NOC (5.5 µmol/kg) than fresh meat (0.5 µmol/kg).124 Pre-agricultural humans consumed their fresh meats along with high intakes s of fresh fruits and vegetables estimated to be between 35-45% of total energy14 compared to 8.1% of total energy in the current U.S. diet.125 Increased fruit and vegetable consumption increases the fecal transit time so that NOC have less contact time with the colonic mucosa and therefore may reduce the carcinogenic risk.126 Hence, the context under which high meat consumption occurred in hunter-gatherers varied significantly from what occurs in westernized populations.
Animal based foods were almost always consumed fresh in conjunction with copious quantities of fresh fruits and vegetables. Even when vegetable intake was low or absent in these peoples, there is little evidence for an association of high protein, animal based diets with colorectal cancer. Prior to western acculturation, the Inuit may have consumed more than 95% of their daily energy from animal and seafood,15 yet a comprehensive review examining virtually all historical and ethnographic data of these people prior to westernization was unable to document a single case of colorectal cancer.126 Should a high protein meat based diet initiate or promote colorectal cancer, then one might expect obligate carnivores such as cats to demonstrate high incidences of these malignancies. In, fact the opposite is true, and the rate of gastrointestinal tract cancers is quite low in domestic cats.128 In summary the case for animal based, high protein diets causing colorectal cancer, within the context of pre-agricultural diets, is weak.
Dietary Protein and Muscle Protein Synthesis and Fatigue
For athletes and individuals engaging in regular exercise, an animal based, high protein diet may be ergogenic and facilitate improved performance because of the stimulatory effect of dietary branch chain amino acids (BCCA) upon muscle protein synthesis,129-131 particularly when they are consumed in the post exercise window.132, 133 Table 2 demonstrates that lean meats and fish are much richer sources of the branch chain amino acids (valine, leucine and isoleucine) than are plant foods. In addition to facilitating muscle synthesis during the post exercise recovery period, BCCA may also improve endurance performance by reducing perceived exertion and mental fatigue by reducing the synthesis of brain 5-hydroxytryptamine, a substance that may promote central fatigue.134
DIETARY PROTEIN: SUMMARY AND CONCLUSIONS
The evolutionary evidence indicates that so called “high protein diets” (20-30% total energy) and “very high protein diets” (30-40% total energy) actually represent the norm which conditioned the present day the human genome over more than 2 million years of evolutionary experience. The evolutionary template would predict that human health and well being will suffer when dietary intakes fall outside this range. Hence the current U.S. consumption of protein (15% total energy) may not optimally promote health and well being. There is now a large body of experimental evidence increasingly demonstrating that a higher intake of lean animal protein reduces the risk for cardiovascular disease, hypertension, dyslipidemia, obesity, insulin resistance, and osteoporosis while not impairing kidney function.
Parts 1, 2, & 3
. Bogert LJ, Briggs GM, Calloway DH. Nutrition and Physical Fitness, Ninth Edition. W.B. Sauders Company, Philadelphia, 1973.
 Dyerberg J, Bang HO. A hypothesis on the development of acute myocardial infarction in Greenlanders. Scand J Clin Lab Invest Suppl. 1982;161:7-13.
 Jenkins DJ, Wolever TM, Taylor RH, Barker H, Fielden H, Baldwin JM, Bowling AC, Newman HC, Jenkins AL, Goff DV. Glycemic index of foods: a physiological basis for carbohydrate exchange. Am J Clin Nutr. 1981 Mar;34(3):362-6.
 No authors listed. Position paper on trans fatty acids. ASCN/AIN Task Force on Trans Fatty Acids. American Society for Clinical Nutrition and American Institute of Nutrition. Am J Clin Nutr. 1996 May;63(5):663-70.
 Willett WC, Stampfer MJ. Rebuilding the food pyramid. Sci Am. 2003 Jan;288(1):64-71
 Krauss RM, Eckel RH, Howard B, et al. Dietary Guidelines: revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation. 2000 Oct 31;102(18):2284-99.
 Blanck HM, Gillespie C, Serdula MK, Khan LK, Galusk DA, Ainsworth BE .Use of low-carbohydrate, high-protein diets among americans: correlates, duration, and weight loss. MedGenMed. 2006 Apr 5;8(2):5.
 Ornish D. Dr. Dean Ornish’s Program for Reversing Heart Disease: The Only System Scientifically Proven to Reverse Heart Disease Without Drugs or Surgery. New York : Random House, 1990.
 Nesse RM, Stearns SC, Omenn GS. Medicine needs evolution. Science 2006;311:1071.
 Dobzhansky T. Am Biol Teacher. 1973 March; 35:125-129.
 Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, O’Keefe JH, Brand-Miller .Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr. 2005 Feb;81(2):341-54.
 Cordain L, Miller JB, Eaton SB, Mann N, Holt SH, Speth JD. Plant-animal subsistence ratios and macronutrient energy estimations in worldwide hunter-gatherer diets. Am J Clin Nutr. 2000 Mar;71(3):682-92.
 Cordain L, Eaton SB, Brand Miller J, Mann N, Hill K. The paradoxical nature of hunter-gatherer diets: Meat based, yet non-atherogenic. Eur J Clin Nutr 2002; 56 (suppl 1):S42-S52.
 Cordain L, Watkins BA, Mann NJ. Fatty acid composition and energy density of foods available to African hominids: evolutionary implications for human brain development. World Rev Nutr Diet 2001, 90:144-161.
 Bravata DM, Sanders L, Huang J, Krumholz HM, Olkin I, Gardner CD, Bravata DM. Efficacy and safety of low-carbohydrate diets: a systematic review.
JAMA. 2003 Apr 9;289(14):1837-50.
 St Jeor ST, Howard BV, Prewitt TE, Bovee V, Bazzarre T, Eckel RH et al.. Dietary protein and weight reduction: a statement for healthcare professionals from the Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association. Circulation. 2001 Oct 9;104(15):1869-74.
 Wright JD, J Kennedy-Stephenson J, Wang CY, McDowell MA, Johnson CL, National Center for Health Statistics, CDC. Trends in intake of energy and macronutrients—United States, 1971-2000. JAMA. 2004;291:1193-1194.
 McDowell M, Briefel R, Alaimo K, et al. Energy and macronutrient intakes of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988–91. Washington, DC: US Government Printing Office, Vital and Health Statistics; 1994. CDC publication No. 255.
 Rudman D, DiFulco TJ, Galambos JT, Smith RB 3rd, Salam AA, Warren WD. Maximal rates of excretion and synthesis of urea in normal and cirrhotic subjects.J Clin Invest. 1973 Sep;52(9):2241-9.
 peth JD, Spielmann KA. Energy source, protein metabolism, and hunter-gatherer subsistence strategies. J Anthropological Archaeology 1983;2:1-31.
 Speth JD. Early hominid hunting and scavenging: the role of meat as an energy source. J Hum Evol 1989;18:329-43.
 Noli D, Avery G. Protein poisoning and coastal subsistence. J Archaeological Sci 1988;15:395-401.
 Lieb CW. The effects on human beings of a twelve months’ exclusive meat diet. JAMA 1929;93:20-22.
 Ogden CL, Fryar CD, Carroll MD, Flegal KM. Mean body weight, height and body mass index, United States 1960—2002 . Center for Disease Control. Advance Data from Vital and Health Statistics, No. 347, October 27, 2004.
 Oliver WJ, Cohen EL, Neel JV. Blood pressure, sodium intake, and sodium related hormones in the Yanomamo Indians, a “no-salt” culture. Circulation. 1975 Jul;52(1):146-51.
Semaw S, Rogers MJ, Quade J, Renne PR, Butler RF, Dominguez-Rodrigo M, Stout D, Hart WS, Pickering T, Simpson SW. 2.6-Million-year-old stone tools and associated bones from OGS-6 and OGS-7, Gona, Afar, Ethiopia. J Hum Evol. 2003 Aug;45(2):169-77.
Bunn, HT, Kroll EM. Systematic butchery by Plio-Pleistocene hominids at Olduvai Gorge, Tanzania. Curr Anthropol 1986;20:365–398.
de Heinzelin J, Clark JD, White T, Hart W, Renne P, WoldeGabriel G, Beyene Y, Vrba E. Environment and behavior of 2.5-million-year-old Bouri hominids. Science. 1999 Apr 23;284(5414):625-9
Asfaw B. White T, Lovejoy O, Latimer B, Simpson S, Suwa, G. Australopithecus garhi: A new species of early hominid from Ethiopia. Science 1999; 284, 629–635.
Vekua A, Lordkipanidze D, Rightmire GP, Agusti J, Ferring R, Maisuradze G, Mouskhelishvili A, Nioradze M, De Leon MP, Tappen M, Tvalchrelidze M, Zollikofer C. A new skull of early Homo from Dmanisi, Georgia. Science. 2002 Jul 5;297(5578):85-9.
Zhu RX, Potts R, Xie F. Hoffman KA, Deng CL, Shi CD, Pan YX, Wang HQ, Shi, RP, Wang YC, Shi GH, Wu NQ. New evidence on the earliest human presence at high northern latitudes in northeast Asia. Nature 2004; 431: 559–562.
Aiello LC, Wheeler P. The expensive tissue hypothesis. Curr Anthropol 1995; 36:199–222.
Leonard W.R, Robertson ML. Evolutionary perspectives on human nutrition: The influence of brain and body size on diet and metabolism. Am J Hum Biol 1994; 6: 77–88.
Pawlosky R., Barnes A., Salem, N. Essential fatty acid metabolism in the feline: Relationship between liver and brain production of long-chain polyunsaturated fatty acids. J Lipid Res 1994;35: 2032–2040.
Hussein N, Ah-Sing E, Wilkinson P, Leach C, Griffin BA, Millward DJ. Long-chain conversion of [13C] linoleic acid and alpha-linolenic acid in response to marked changes in their dietary intake in men. J Lipid Res. 2005 Feb;46(2):269-80.
Sturman JA, Hepner GW, Hofmann AF, Thomas PJ. Metabolism of [35S] taurine in man. J Nutr. 1975 Sep;105(9):1206-14.
Chesney RW, Helms RA, Christensen M, Budreau AM, Han X, Sturman JA. The role of taurine in infant nutrition. Adv Exp Med Biol. 1998;442:463-76.
Laidlaw SA, Shultz TD, Cecchino JT, Kopple JD. Plasma and urine taurine levels in vegans. Am J Clin Nutr. 1988 Apr;47(4):660-3.
Knopf K, Sturman JA, Armstrong M, Hayes KC. 1978. Taurine: An essential nutrient for the cat. J Nutr 1978;108: 773–778.
MacDonald ML, Rogers QR, Morris JG. Nutrition of the domestic cat, a mammalian carnivore. Annu Rev Nutr 1984; 4: 521–562.
Fam AG. Gout: excess calories, purines, and alcohol intake and beyond. Response to a urate-lowering diet. J Rheumatol. 2005 May;32(5):773-7.
Matzkies F, Berg G, Madl H. The uricosuric action of protein in man. Adv Exp Med Biol 1980;122A:227-31.
Loffler W. Grobner W, Medina R, Zollner N. Influence of dietary purines on pool size, turnover, and excretion of uric acid during balance conditions. Isotope studies using 15N-uric acid. Res Exp Med (Berl). 1982(2):113-123.
Oda M, Satta Y, Takenaka O, Takahata N. Loss of urate oxidase activity in hominoids and its evolutionary implications. Mol Biol Evol. 2002 May; 19(5): 640-53.
Abadeh S, Killacky J, Benboubetra M, Harrison R. Purification and partial characterization of xanthine oxidase from human milk. Biochim Biophys Acta. 1992 Jul 21;1117(1):25-32
Xu P, LaVallee P, Hoidal JR. Repressed expression of the human xanthine oxidoreductase gene. E-box and TATA-like elements restrict ground state transcriptional activity. J Biol Chem. 2000 Feb 25;275(8):5918-26.
Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokgadi J. Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis. 2000 Jul;59(7):539-43.
vTeleki G. The omnivorous chimpanzee. Sci Am 1973; 228: 33–42.
Stanford CB. The hunting ecology of wild chimpanzees: Implications for the evolutionary ecology of Pliocene hominids. Am Anthropol 1996; 98: 96–113.
Schoeninger MJ, Moore J, Sept JM. Subsistence strategies of two “savanna” chimpanzee populations: The stable isotope evidence. Am J Primatol 1999: 49: 297–314.
van der Merwe NJ, Thackeray JF, Lee-Thorp JA, Luyt J. The carbon isotope ecology and diet of Australopithecus africanus at Sterkfontein, South Africa J Hum Evol 2003;44: 581–597.
Lee-Thorp J, Thackeray JF, van der Merwe N. The hunters and the hunted revisited. J Hum Evol 2000; 39: 565–576.
Sponheimer M, Lee-Thorp JA.. Differential resource utilization by extant great apes and australopithecines: Towards solving the C4 conundrum. Comp Biochem Physiol A 2003;136: 27–34.
Sussman RW. Foraging patterns of nonhuman primates and the nature of food preferences in man. Fed Proc 1978;37: 55–60.
Richards MP, Pettitt PB, Trinkaus E, Smith FH, Paunovic M, Karavanic, I. Neanderthal diet at Vindija and Neanderthal predation: The evidence from stable isotopes. Proc Natl Acad Sci 2000;97: 7663–7666.
Bocherens H, Drucker DG, Billiou D, Patou-Mathis M, Vandermeersch B. Isotopic evidence for diet and subsistence pattern of the Saint-Cesaire I Neanderthal: review and use of a multi-source mixing model. J Hum Evol. 2005 Jul;49(1):71-87
Balter V, Simon L. Diet and behavior of the Saint-Cesaire Neanderthal inferred from biogeochemical data inversion. J Hum Evol. 2006 Oct;51(4):329-38.
Currat M, Excoffier L. Modern humans did not admix with Neanderthals during their range expansion into Europe. PLoS Biol. 2004 Dec;2(12):e421. Epub 2004 Nov 30
Richards MP, Hedges REM, Jacobi R, Current, A, Stringer C. Focus: Gough’s Cave and Sun Hole Cave human stable isotope values indicate a high animal protein diet in the British Upper Palaeolithic. J Archaeol Sci 2000;27: 1–3.
Gray JP. A corrected ethnographic atlas. World Cult J 1999;10: 24–85.
Hayden B. Subsistence and ecological adaptations of modern hunter/gatherers. In: RSO Harding, RSO, Teleki G. (Eds.), Omnivorous Primates. Columbia University Press, New York, 1981, pp. 344–421.
Kaplan H, Hill K, Lancaster J, Hurtado AM. A theory of human life history evolution: diet, intelligence, and longevity. Evol. Anthropol 2000;9:156–185.
Kaplan H, Hill K, Lancaster J, Hurtado AM. A theory of human life history evolution: diet, intelligence, and longevity. Evol. Anthropol 2000;9:156–185.
Sempos CT, Liu K, Ernst ND. Food and nutrient exposures: what to consider when evaluating epidemiologic evidence. Am J Clin Nutr. 1999 Jun;69(6):1330S-1338S.
Potischman N, Weed DL. Causal criteria in nutritional epidemiology. Am J Clin Nutr. 1999 Jun;69(6):1309S-1314S.
Freudenheim JL. Study design and hypothesis testing: issues in the evaluation of evidence from research in nutritional epidemiology. Am J Clin Nutr. 1999 Jun; 69(6): 1315S-1321S.
Fraser GE. A search for truth in dietary epidemiology. Am J Clin Nutr. 2003 Sep;78(3 Suppl):521S-525S.
Flegal KM. Evaluating epidemiologic evidence of the effects of food and nutrient exposures. Am J Clin Nutr. 1999 Jun;69(6):1339S-1344S.
Hu FB, Stampfer MJ, Manson JE, Rimm E, Colditz GA, Speizer FE, Hennekens CH, Willett WC. Dietary protein and risk of ischemic heart disease in women. Am J Clin Nutr. 1999 Aug;70(2):221-7.
Campbell TC, Junshi C. Diet and chronic degenerative diseases: perspectives from China. Am J Clin Nutr. 1994 May;59(5 Suppl):1153S-1161S.
Campbell TC, Parpia B, Chen J. Diet, lifestyle, and the etiology of coronary artery disease: the Cornell China study. Am J Cardiol. 1998 Nov 26;82(10B):18T-21T.
Popkin BM. Where’s the fat? Trends in U.S. Diets 1965-1996. Prev Med 2001;32:245-54.
Wolfe BM & Giovannetti PM (1991): Short term effects of substituting protein for carbohydrate in the diets of moderately hypercholesterolemic human subjects. Metabolism 40, 338-343.
Wolfe BM & Piche LA (1999): Replacement of carbohydrate by protein in a conventional-fat diet reduces cholesterol and triglyceride concentrations in healthy normolipidemic subjects. Clin. Invest. Med. 22, 140-148.
O’Dea K (1984): Marked improvement in carbohydrate and lipid metabolism in diabetic Australian Aborigines after temporary reversion to traditional lifestyle. Diabetes 33, 596-603.
O’Dea K, Traianedes K, Ireland P, Niall M, Sadler J, Hopper J & DeLuise M (1989): The effects of diet differing in fat, carbohydrate, and fiber on carbohydrate and lipid metabolism in type II diabetes. J. Am. Diet. Assoc. 89, 1076-1086.
Layman DK, Boileau RA, Erickson DJ, Painter JE, Shiue H, Sather C, Christou DD. A reduced ratio of dietary carbohydrate to protein improves body composition and blood lipid profiles during weight loss in adult women. J Nutr. 2003 Feb;133(2):411-7.
Noakes M, Keogh JB, Foster PR, Clifton PM. Effect of an energy-restricted, high-protein, low-fat diet relative to a conventional high-carbohydrate, low-fat diet on weight loss, body composition, nutritional status, and markers of cardiovascular health in obese women. Am J Clin Nutr. 2005 Jun;81(6):1298-306.
Farnsworth E, Luscombe ND, Noakes M, Wittert G, Argyiou E, Clifton PM. Effect of a high-protein, energy-restricted diet on body composition, glycemic control, and lipid concentrations in overweight and obese hyperinsulinemic men and women. Am J Clin Nutr. 2003 Jul;78(1):31-9.
Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Foster P, Clifton PM. Carbohydrate-restricted diets high in either monounsaturated fat or protein are equally effective at promoting fat loss and improving blood lipids. Am J Clin Nutr. 2005 Apr;81(4):762-72
Aude YW, Agatston AS, Lopez-Jimenez F, Lieberman EH, Marie Almon, Hansen M, Rojas G, Lamas GA, Hennekens CH. The national cholesterol education program diet vs a diet lower in carbohydrates and higher in protein and monounsaturated fat: a randomized trial. Arch Intern Med. 2004 Oct 25;164(19):2141-6.
McAuley KA, Hopkins CM, Smith KJ, McLay RT, Williams SM, Taylor RW, Mann JI. Comparison of high-fat and high-protein diets with a high-carbohydrate diet in insulin-resistant obese women. Diabetologia. 2005 Jan;48(1):8-16.
Appel LJ, Sacks FM, Carey VJ, Obarzanek E, Swain JF, Miller ER 3rd, Conlin PR, Erlinger TP, Rosner BA, Laranjo NM, Charleston J, McCarron P, Bishop LM; OmniHeart Collaborative Research Group. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA. 2005 Nov 16;294(19):2455-64.
Kalopissis, AD Griffaton G, Fau D. Inhibition of hepatic very low density lipoprotein secretion on obese Zucker rats adapted to a high protein diet. Metabolism 1995;44:19-29.
Appel LJ. The effects of protein intake on blood pressure and cardiovascular disease. Curr Opin Lipidol. 2003 Feb;14(1):55-9. Review.
Elliott P. Protein intake and blood pressure in cardiovascular disease. Proc Nutr Soc. 2003 May;62(2):495-504.
He J, Whelton PK. Elevated systolic blood pressure as a risk factor for cardiovascular and renal disease. J Hypertens Suppl. 1999 Jun;17(2):S7-13.
Burke V, Hodgson JM, Beilin LJ, Giangiulioi N, Rogers P, Puddey IB. Dietary protein and soluble fiber reduce ambulatory blood pressure in treated hypertensives. Hypertension. 2001 Oct;38(4):821-6.
Washburn S, Burke GL, Morgan T, Anthony M. Effect of soy protein supplementation on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women. Menopause. 1999 Spring;6(1):7-13.
He J, Gu D, Wu X, Chen J, Duan X, Chen J, Whelton PK. Effect of soybean protein on blood pressure: a randomized, controlled trial.Ann Intern Med. 2005 Jul 5;143(1):1-9.
Hodgson JM, Burke V, Beilin LJ, Puddey IB. Partial substitution of carbohydrate intake with protein intake from lean red meat lowers blood pressure in hypertensive persons. Am J Clin Nutr. 2006 Apr;83(4):780-7
Nuttall FQ, Gannon MC. The metabolic response to a high-protein, low-carbohydrate diet in men with type 2 diabetes mellitus. Metabolism. 2006 Feb;55(2):243-51.
Nuttall FQ, Gannon MC. Metabolic response of people with type 2 diabetes to a high protein diet. Nutr Metab (Lond). 2004 Sep 13;1(1):6
McAuley KA, Smith KJ, Taylor RW, McLay RT, Williams SM, Mann JI. Long-term effects of popular dietary approaches on weight loss and features of insulin resistance. Int J Obes (Lond). 2006 Feb;30(2):342-9.
Weigle DS, Breen PA, Matthys CC, Callahan HS, Meeuws KE, Burden VR, Purnell JQ. A high-protein diet induces sustained reductions in appetite, ad libitum caloric intake, and body weight despite compensatory changes in diurnal plasma leptin and ghrelin concentrations. Am J Clin Nutr. 2005 Jul;82(1):41-8
Due A, Toubro S, Skov AR, Astrup A. Effect of normal-fat diets, either medium or high in protein, on body weight in overweight subjects: a randomised 1-year trial. Int J Obes Relat Metab Disord. 2004 Oct;28(10):1283-90
Westerterp-Plantenga MS, Lejeune MP, Nijs I, van Ooijen M, Kovacs EM. High protein intake sustains weight maintenance after body weight loss in humans. Int J Obes Relat Metab Disord. 2004 Jan;28(1):57-64.
Lejeune MP, Kovacs EM, Westerterp-Plantenga MS. Additional protein intake limits weight regain after weight loss in humans. Br J Nutr. 2005 Feb;93(2):281-9.
Porrini M, Santangelo A, Crovetti R, Riso P, Testolin G, Blundell JE. Reid M, Hetherington M. Relative effects of carbohydrates and protein on satiety — a review of methodology. Neurosci Biobehav Rev 1997 May;21(3):295-308
Poppitt SD, McCormack D, Buffenstein R. Short-term effects of macronutrient preloads on appetite and energy intake in lean women. Physiol Behav 1998 Jun 1;64(3):279-85
Batterham RL, Heffron H, Kapoor S, Chivers JE, Chandarana K, Herzog H, Le Roux CW, Thomas EL, Bell JD, Withers DJ. Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab. 2006 Sep;4(3):223-33.
O’Brien KO, Abrams SA, Liang LK, Ellis KJ, Gagel RF. Increased efficiency of calcium absorption during short periods of inadequate calcium intake in girls. Am J Clin Nutr. 1996 Apr;63(4):579-83
Dawson-Hughes B, Harris SS, Rasmussen H, Song L, Dallal GE. Effect of dietary protein supplements on calcium excretion in healthy older men and women. J Clin Endocrinol Metab. 2004 Mar;89(3):1169-73
Spencer H, Kramer L, Osis D, Norris C. Effect of a high protein (meat) intake on calcium metabolism in man. Am J Clin Nutr. 1978 Dec;31(12):2167-80
Roughead ZK, Johnson LK, Lykken GI, Hunt JR. Controlled high meat diets do not affect calcium retention or indices of bone status in healthy postmenopausal women. J Nutr. 2003 Apr;133(4):1020-6
Arjmandi BH, Khalil DA, Smith BJ, Lucas EA, Juma S, Payton ME, Wild RA. Soy protein has a greater effect on bone in postmenopausal women not on hormone replacement therapy, as evidenced by reducing bone resorption and urinary calcium excretion. J Clin Endocrinol Metab. 2003 Mar;88(3):1048-54
Pannemans DL, Schaafsma G, Westerterp KR. Calcium excretion, apparent calcium absorption and calcium balance in young and elderly subjects: influence of protein intake. Br J Nutr. 1997 May;77(5):721-9.
Kerstetter JE, O’Brien KO, Insogna KL. Dietary protein affects intestinal calcium absorption. Am J Clin Nutr. 1998 Oct;68(4):859-65.
Kerstetter JE, O’Brien KO, Caseria DM, Wall DE, Insogna KL. The impact of dietary protein on calcium absorption and kinetic measures of bone turnover in women. J Clin Endocrinol Metab. 2005 Jan;90(1):26-31.
Kerstetter JE, Wall DE, O’Brien KO, Caseria DM, Insogna KL. Meat and soy protein affect calcium homeostasis in healthy women. J Nutr. 2006 Jul;136(7):1890-5
Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease.N Engl J Med. 1982 Sep 9;307(11):652-9.
Lippert J, Ritz E, Schwarzbeck A, Schneider P. The rising tide of endstage renal failure from diabetic nephropathy type II–an epidemiological analysis. Nephrol Dial Transplant. 1995;10(4):462-7.
Ritz E, Rychlik I, Locatelli F, Halimi S. End-stage renal failure in type 2 diabetes: A medical catastrophe of worldwide dimensions. Am J Kidney Dis. 1999 Nov;34(5):795-808.
Wrone EM, Carnethon MR, Palaniappan L, Fortmann SP; Third National Health and Nutrition Examination Survey. Association of dietary protein intake and microalbuminuria in healthy adults: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003 Mar;41(3):580-7.
Johnson DW. Dietary protein restriction as a treatment for slowing chronic kidney disease progression: the case against. Nephrology. 2006 Feb;11(1):58-62.
Skov AR, Toubro S, Bulow J, Krabbe K, Parving HH, Astrup A. Changes in renal function during weight loss induced by high vs low-protein low-fat diets in overweight subjects. Int J Obes Relat Metab Disord. 1999 Nov;23(11):1170-7.
Bingham SA. High-meat diets and cancer risk. Proc Nutr Soc. 1999 May;58(2):243-8.
Truswell AS. Meat consumption and cancer of the large bowel. Eur J Clin Nutr. 2002 Mar;56 Suppl 1:S19-24.
Larsson SC, Wolk A. Meat consumption and risk of colorectal cancer: A meta-analysis of prospective studies.Int J Cancer. 2006 Sep 21; [Epub ahead of print]
Bingham SA, Hughes R, Cross AJ. Effect of white versus red meat on endogenous N-nitrosation in the human colon and further evidence of a dose response. J Nutr. 2002 Nov;132(11 Suppl):3522S-3525S
Lunn JC, Kuhnle G, Mai V, Frankenfeld C, Shuker DE, Glen RC, Goodman JM, Pollock JR, Bingham SA. The effect of haem in red and processed meat on the endogenous formation of N-nitroso compounds in the upper gastrointestinal tract. Carcinogenesis. 2006 Oct 19; [Epub ahead of print].
Haorah J, Zhou L, Wang X, Xu G, Mirvish SS. Determination of total N-nitroso compounds and their precursors in frankfurters, fresh meat, dried salted fish, sauces, tobacco, and tobacco smoke particulates. J Agric Food Chem. 2001 Dec;49(12):6068-78
Gerrior S, Bente I. 2002. Nutrient Content of the U.S. Food Supply, 1909-99: A Summary Report. U.S.D.A, Center for Nutrition Policy and Promotion. Home Economics Research Report No. 55.
Hughes R, Pollock JR, Bingham S. Effect of vegetables, tea, and soy on endogenous N-nitrosation, fecal ammonia, and fecal water genotoxicity during a high red meat diet in humans. Nutr Cancer. 2002;42(1):70-7.
Stefansson V. Cancer: Disease of Civilization. Hill and Wang, New York, 1960.
Patnaik AK, Liu SK, Johnson GF. Feline intestinal adenocarcinoma. A clinicopathologic study of 22 cases. Vet Pathol. 1976;13(1):1-10
Anthony JC, Lang CH, Crozier SJ, Anthony TG, MacLean DA, Kimball SR, Jefferson LS. Contribution of insulin to the translational control of protein synthesis in skeletal muscle by leucine. Am J Physiol Endocrinol Metab. 2002;282:E1092-101.
Layman DK. Role of leucine in protein metabolism during exercise and recovery. Can J Appl Physiol 2002;27:646-62.
Rasmussen BB, Tipton KD, Miller SL, Wolf SE, Wolfe RR. An oral essential amino acid-carbohydrate supplement enhances muscle protein anabolism after resistance exercise.J Appl Physiol. 2000 Feb;88(2):386-92.
Tipton KD, Rasmussen BB, Miller SL, Wolf SE, Owens-Stovall SK, Petrini BE, Wolfe RR. Timing of amino acid-carbohydrate ingestion alters anabolic response of muscle to resistance exercise. Am J Physiol Endocrinol Metab. 2001 Aug;281(2):E197-206.
Levenhagen DK, Gresham JD, Carlson MG, Maron DJ, Borel MJ, Flakoll PJ. Postexercise nutrient intake timing in humans is critical to recovery of leg glucose and protein homeostasis. Am J Physiol Endocrinol Metab. 2001;280:E982-93.
Blomstrand E. Amino acids and central fatigue. Amino Acids 2001;20:25-34.