Effects of whey protein supplements on metabolism: evidence

from human intervention studies

Sonja Grafa, Sarah Egerta and Martina Heerb
a
Department of Nutrition and Food Science, Nutritional
Physiology, University of Bonn, Bonn and bProfil
Institute for Metabolic Research GmbH, Neuss,
Germany
Correspondance to Martina Heer, Profil Institute for
Metabolic Research GmbH, Hellersbergstr. 9, 41460
Neuss, Germany
Tel: +49 2131 4018 253; fax: +49 2131 4018 553;
e-mail: Martina.Heer@profil.com
Current Opinion in Clinical Nutrition and
Metabolic Care 2011, 14:569580
Purpose of review
Epidemiological studies indicate that the consumption of milk and dairy products is
inversely associated with a lower risk of metabolic disorders and cardiovascular
diseases. In particular, whey protein seems to induce these effects because of bioactive
compounds such as lactoferrin, immunoglobulins, glutamine and lactalbumin. In
addition, it is an excellent source of branch chained amino acids. This review
summarizes recent findings on the effects of whey protein on metabolic disorders and
the musculoskeletal system.
Recent findings
We identified 25 recently published intervention trials examining chronic and/or acute
effects of whey protein supplementation on lipid and glucose metabolism, blood
pressure, vascular function and on the musculoskeletal system. Whey protein appears
to have a blood glucose and/or insulin lowering effect partly mediated by incretins. In
addition, whey protein may increase muscle protein synthesis. In contrast there are no
clear-cut effects shown on blood lipids and lipoproteins, blood pressure and vascular
function. For bone metabolism the data are scarce.
Summary
In summary, whey protein may affect glucose metabolism and muscle protein synthesis.
However, the evidence for a clinical efficacy is not strong enough to make final
recommendations with respect to a specific dose and the duration of supplementation.

Keywords
glucose metabolism, incretins, lipid metabolism, musculoskeletal system, vascular
function, whey protein

Curr Opin Clin Nutr Metab Care 14:569580

2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
1363-1950

teins [8,9
], glycaemia and insulin [10], vascular function

Introduction
Epidemiological studies indicate that the consumption
of milk and dairy products is inversely associated with
a lower risk of metabolic disorders and cardiovascular
diseases [1,2]. Dairy proteins in bovine milk are com-
prised approximately 80% casein and approximately
20% whey protein. Both types of proteins are hetero-
geneous groups of proteins and are rich in indispensable
amino acids, which have been described as essential
amino acids in the past [3,4]. It has been shown that
whey proteins are more effective on the respective phys-
iological systems than casein, most likely because of the
faster digestion and absorption kinetics [57]. Whey
protein also includes bioactive components such as
lactoferrin, immunoglobulins, glutamine, lactalbumin
and is an excellent source of branch chained amino acids
(BCAAs) [1], which could play a further role in its
physiological effects.
Recent clinical evidence indicates that whey proteins
may have beneficial effects on serum lipids and lipopro-
1363-1950 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
and blood pressure [9
] as well as bone metabolism [11]
and muscle protein synthesis (MPS) [12
].
Results of randomized controlled intervention
studies
This section summarizes and evaluates the results of
recent controlled human trials that examined the pre-
ventive and therapeutic effects of whey protein on meta-
bolic disorders, such as dyslipidemia and impaired glu-
cose tolerance, vascular function as well as effects on the
musculoskeletal system.
Effects of whey protein on lipid metabolism
The potential lipid-lowering effects of whey protein
have been examined in five trials with inconsistent
results [1315,16

,17

] (Table 1). Two of these studies
did not find any effects of a regular whey protein supple-
mentation (612 weeks) on lipid metabolism when com-
pared to control or casein [13,14]. In contrast, one study
showed a decrease in fasting plasma concentrations of
DOI:10.1097/MCO.0b013e32834b89da

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 Table 1 Randomized controlled intervention studies about the effects of whey protein on parameters of lipid metabolism
Reference Study design Individuals analyzed Supplementation and duration Parameters Significant effects of intervention
570 Functional foods

Claessens Randomized, diet-controlled, 48 overweight and obese Energy restriction period (56 weeks), Fasting plasma concentrations No difference between whey
et al. [14] single-blind, parallel, individuals, mean age weight maintenance (12 weeks): of TC, LDL, HDL, TAG, FFAs or casein-supplemented
four groups 45.4 years, mean low-fat diet and maltodextrin groups
BMI 32.9 kg/m2 (high-carbohydrate group) or
protein (high-protein group):
casein (HPC subgroup) or whey
(HPW subgroup) supplements
2 25 g/day
Fluegel Randomized, controlled, 71 normotensive, prehypertensive, 28 g/day of either hydrolyzed whey Concentrations of TC, LDL, Compared to control,
et al. [13] parallel, two groups and stage 1 hypertensive protein concentrate (n 36) or TAG hydrolyzed whey protein
individuals, mean age 20.6 years, nonhydrolyzed whey protein did not affect TC, LDL, TAG
mean BMI 24.7 kg/m2 concentrate (n 35, control) in # in TC and LDL after combining
a fruit flavored beverage; 6 weeks data of both whey beverages
Mortensen Randomized, controlled, 12 type 2 diabetic patients Test meal: energy-free soup Fasting and postprandial iAUC for TAG was lower after
et al. [15] crossover, four treatments (6 women, 6 men), mean age 100 g butter (80% fat) white plasma concentrations of whey-meal than after the
64.6 years, mean BMI 28.9 kg/m2 bread (45% carbohydrates) TAG, TC, HDL, FFAs, RP other meals
45 g of respective protein RP response was lower after
(gluten, cod, casein or whey) whey-meal than after
24 h before standard diet of 7000 kJ cas-meal and cod-meal in
for women, 9000 kJ for men the chylomicron-rich fraction
and higher after the whey meal
than after cod and glu-meals
in the chylomicron-poor fraction
FFAs were most pronouncedly
suppressed after the whey-meal
Pal et al. [16

] Randomized, parallel, single- 70 overweight and obese 54 g of either whey protein isolate Fasting plasma concentrations Whey protein # TAG at week 6
blind, three treatments individuals, age 1865 years, or sodium caseinate application of TC, LDL, HDL, TAG, and week 12 compared to
of 12 weeks each BMI 2540 kg/m2 versus control (glucose) FFAs, Apo B control
Whey protein # TC and LDL
at week 12 compared to
casein and control groups
Pal et al. [17

] Randomized, controlled, 20 overweight and obese 45 g whey protein isolate or 45 g Fasting and postprandial serum Whey protein # AUC for TAG
single blind, crossover, postmenopausal women, age sodium caseinate or 45 g glucose concentrations of TC, LDL, compared to glucose and
three treatments <66 years, BMI 2540 kg/m2 control mixed with water and HDL, TAG, FFAs, apo B48 caseine
consumed with a breakfast meal; Whey protein # TAG:apoB
standardized evening meal before 48 ratio compared to glucose
the intervention day, 6-h test period and caseine

Apo, apolipoprotein; FFAs, free fatty acids; HDL, high-density lipoprotein cholesterol; iAUC, incremental area under the curve; LDL, low-density lipoprotein cholesterol; RP, retinyl palmitate; TAG, triacylglycerol; TC, total cholesterol.

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triacylglycerols (TAGs) after long-term whey protein
intake (12 weeks) in overweight and obese individuals
[16

].
In two trials, the acute effects of whey on postprandial
lipid metabolism were examined [15,17

]: in overweight
and obese postmenopausal women, a single oral dose of
45 g whey protein isolate reduced postprandial TAG
concentrations as measured by area under the curve
(AUC) after a high-fat meal when compared to 45 g casein
or glucose. Similar to this study, Mortensen et al. [15]
found that 45 g of whey added to a fat-rich meal produced
a lower TAG response when compared to 45 g casein, cod
or gluten protein, respectively, in individuals with type 2
diabetes mellitus (T2DM).
The mechanisms explaining the effects of whey protein
on TAG metabolism are not well understood. Mortensen
et al. [15] proposed that the whey meal may have resulted
in a reduced production of chylomicrons. They also
suggest that whey may stimulate the lipoprotein lipase
which in turn accelerates chylomicron clearance [15]. Pal
et al. [17

] speculated that the reduction in circulating
TAG-rich chylomicrons from whey protein consumption
could be due to its effects on digestion or absorption rates
[18,19].
In both acute studies [15,17

] there were no effects of
whey protein on total cholesterol, LDL and HDL choles-
terol. This is in accordance with most of the long-term
studies (Table 1). Only one study showed that regular
consumption of whey protein isolate (54 g/day) over
12 weeks reduced fasting total and LDL cholesterol in
overweight and obese individuals when compared with
control and casein [16

]. The decrease in LDL choles-
terol with whey protein was observed without changes in
concentrations of apolipoprotein B, indicating a change in
LDL size rather than in LDL particle number. Potential
mechanisms behind the effects of whey protein on LDL
cholesterol may be mediated, at least in part, by the
inhibition of the hepatic cholesterol synthesis [20] and/or
the inhibition of the expression of genes involved in
intestinal fatty acid and cholesterol absorption and syn-
thesis [21].
Effects of whey protein on glucose metabolism
In recent years a lot of importance was attached to the
effects of whey protein on glucose and insulin metab-
olism [10,14,15,16

,2229] (Table 2). Most of these
showed a decrease in blood glucose and/or insulin. In
former studies it has been demonstrated that milk
proteins have insulinotropic properties and that in
particular the whey fraction being a more insulin secre-
tagogue than casein [19]. This insulinotropic effect has
mainly been examined in metabolically healthy people
[10,2224,26], but has also been shown in T2DM [25,30].
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Effects of whey protein supplements on metabolism Graf et al. 571
It has been suggested [19] that the higher content of the
BCAAs leucin and isoleucin in whey protein is the main
driver for increased insulin release compared to non-
BCAAs. However, a mixture of these BCAAs did not
achieve the same magnitude of change as whey protein
does [31]. But, there seems to be a dose-dependent
effect. When acutely applying different amounts of whey
protein before or together with a high carbohydrate
containing test meal, amounts of more than 20 g/serving
led to more pronounced effects in lowering blood glucose
and increasing insulin and glucagon levels compared to
5 and 10 g application [22,26].
The potential of whey protein as compared to other
protein sources such as egg, turkey, and fish protein
has been examined by Pal and Ellis [10] in healthy
individuals. Whey protein application led to an approxi-
mately 10% lower AUC for plasma glucose and an
approximately 200% higher AUC for insulin compared
to egg albumin [10]. Thereby the magnitude of blood
glucose reduction after whey protein application is com-
parable to that which is hoped for a pharmaceutical
treatment such as sulfonylureas and therefore is support-
ing a considerable implication of this dietary treatment on
the management of T2DM [25]. Following whey protein
application both glucagon-like peptide-1 (GLP-1) and
glucose-dependent insulinotropic polypeptide (GIP)
levels were increased in both healthy and T2DM patients
suggesting further insulin secretion and/or glucagon syn-
thesis inhibition [25,28].
In the above-summarized publications only acute effects
have been tested. However, for long-term implications
longer periods of examinations are mandatory. Hence,
only two further studies focused on long-term effects
(7 days [24] and 12 weeks [16

]) in overweight/obese
adults. At the end of the 12-week whey protein appli-
cation (54 g/day) in adults [16

] fasting plasma insulin
levels were decreased by 11% and the homeostasis model
assessment of insulin resistance score by 10% compared
with baseline [16

] suggesting an increase in insulin
sensitivity. In young boys (8 years), whey protein appli-
cation of 10.5 g/day for 7 days increased fasting insulin by
21% without affecting fasting blood glucose, thereby
suggesting an increase in insulin resistance [24].
Effects of whey protein on blood pressure and vascular
function
We identified six intervention studies, two of them
including a postprandial protocol [9
,32], investigating
the effects of whey protein on blood pressure (BP) and/
or vascular endothelial function [9
,13,14,32,33,34

]
(Table 3). Their results are conflicting. Two studies
found a decrease in resting BP after whey protein intake
[13,34

], two studies showed an improvement in vascular
function measured by flow-mediated dilation and pulse
 Table 2 Randomized controlled intervention studies about the effects of whey protein on parameters of glucose and insulin metabolism
Reference Study design Individuals analyzed Supplementation and duration Parameters Significant effects of intervention

Akhavan Randomized, controlled crossover, 37 healthy individuals, Experiment 1 and control: premeal Blood glucose to insulin ratio, Premeal whey protein intake
et al. [22] 2 3 treatments; examination mean age 22.05 years, load: 10, 20, 30 and 40 g iAUC for glucose and insulin (10, 20, and 40 g) " pre meal
572 Functional foods

of acute effects mean BMI 22.35 kg/m2 whey protein insulin levels; postmeal iAUC
Experiment 2: premeal load: 5, 10, (095 min) for glucose and
20, and 40 g whey protein and insulin (30170 min) # dose-
10 g whey protein hydrolysate dependently; less pronounced
effect with whey protein
hydrolysate
Claessens Randomized, controlled, parallel; Two groups of 12 healthy Group 1: 0.3, 0.4 or 0.6 g/kg body Plasma glucose, insulin, Insulin and glucagon levels "
et al. [29] examination of acute effects individuals each, mean age: weight were tested as intact glucagon following high protein intake;
25.9 years, mean BMI soya protein or hydrolysate no significant difference in
23 kg/m2 Group 2: 0.3, 0.4 or 0.6 g/kg body plasma insulin, glucose or
weight were tested as intact glucagon levels between intact
whey protein or hydrolysate or hydrolyzed whey protein
application
Claessens Randomized, controlled, single-blind, 8 healthy men, mean age Per bolus 0.2 g/kg body weight as Plasma glucose, insulin, Insulin levels " with protein
et al. [23] crossover, separation of tests by 32 years, mean BMI: protein hydrolysate of pea, rice, glucagon hydolysate intake and peaked
at least 2 days; examination of 23.7 kg/m2 soy, gluten, whey, egg provided at t 30 min; all protein
acute effects in a drink hydrolysate mixtures " iAUC
of glucagon
Claessens Randomized, diet-controlled, 48 overweight and obese Energy restriction period (56 weeks), Fasting plasma concentrations No difference between the whey
et al. [14] single-blind, parallel, four groups individuals, mean age weight maintenance (12 weeks): of glucagon, insulin, HOMAir or casein-supplemented groups
45.4 years, mean low-fat diet and maltodextrin Index; HbA1c
BMI 32.9 kg/m2 (high-carbohydrate group) or
protein (high-protein group): casein
(HPC subgroup) or whey
(HPW subgroup) supplements
2 25 g/day
Frid et al. [30] Randomized, controlled, single-blind, 14 diet treated individuals with Test meal: breakfast: four slices (102 g) Blood glucose, serum insulin, No significant treatment effect
crossover; separation of tests by type 2 diabetes, 2769 years, of white bread 300 ml water; lunch: AUC glucose, AUC insulin, following breakfast for glucose
at least 1 week; examination of mean BMI: 26.2 kg/m2 52.2 g instant potato powder GLP-1, GIP, AUC GLP-1, and insulin, but after lunch;
acute effects 270 ml boiling water 50 g meatballs AUC GIP AUC insulin " and AUC GIP "
300 ml water; one occasion: 27.6 g after breakfast and lunch with
of whey protein (breakfast and lunch); whey protein application;
other occasion: 96 g lean ham no significant difference in
5.3 g lactose dissolved in water GLP-1 concentrations following
breakfast
Hoppe Randomized, double-blind, 57 healthy, 8-year-old boys Protein supplementation daily for Fasting plasma glucose and b-Cell function " because of
et al. [24] 2  2 factorial design completed the study of which 7 days was 10.5 g of whey insulin levels, HOMA index, mineral intervention; not further
three were overweight and protein low milk mineral content HOMA beta cell function, effect because of mineral
three obese (40 mg calcium 47 mg phosphate), disposition index intervention; whey protein led
10.5 g whey high milk mineral to " fasting insulin levels;
content (1860 mg calcium 883 mg HOMA-IR "; HOMA b-cell
phosphate), 42 g casein low milk function "; plasma glucose
mineral content; 42 g casein levels were unaffected;
high milk mineral content disposition index was not
different in whey compared to
casein interventions

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 Ma et al. [25] Randomized, controlled crossover;
three interventions study;
examination of acute effects
Mortensen Randomized, controlled, crossover,
et al. [15] four treatments
Nilsson Randomized, controlled, crossover,
et al. [19] seven treatments; time between
treatments >1 week; examination
of acute effects
Nilsson Randomized, controlled, crossover;
et al. [31] five interventions; time between
intervention: 1 week; examination
of acute effects
Pal and Randomized, single-blind, controlled,
Ellis [10] crossover; four interventions;
time between treatments: 1 week;
examination of acute effects
Pal et al. [16

] Randomized, parallel, single-blind,
three interventions of 12 weeks each
Petersen Randomized, controlled, crossover;
et al. [26] four interventions; repetitions per
intervention: 2; time between
intervention >1 day; examination
of acute effects
Power Randomized, controlled, crossover;
et al. [27] two interventions, time between
intervention: 7 days; examination
of acute effects
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8 dietary controlled type 2
diabetic patients (seven male,
one female), mean age
58 years, mean BMI 28.6 kg/m2
12 type 2 diabetic patients
(six women, six men), mean age:
64.6 years, mean BMI 28.9 kg/m2
12 healthy, nonsmoking individuals,
age 2028 years, mean BMI
21.9 kg/m2
12 healthy individuals,
age 2030 years,
mean BMI 22.4 kg/m2
22 healthy men, mean age:
22.9 years, mean BMI: 22.6 kg/m2
70 overweight and obese individuals,
age 1865 years, BMI 2540 kg/m2
10 healthy individuals, mean age
44.4 years, mean BMI 33.6 kg/m2
16 healthy individuals, mean age
22.4 years, mean BMI 23.2 kg/m2
Interventions: beef-flavored soup
30 min before mashed potato meal;
beef-flavored soup 55 g whey
protein 30 min before mashed potato
meal; beef-flavored soup 30 min
before mashed potato meal 55 g
whey protein
Test meal: energy-free soup 100 g
butter (80% fat) white bread
(45% carbohydrates) 45 g of
respective protein (gluten, cod,
casein or whey)
Treatments with different protein
sources: white wheat bread
(25 g carbohydrates, 2.8 g
protein; gluten low: 25 g
carbohydrates, 2.8 g protein;
gluten high: 25 g carbohydrates,
18.2 g protein; cod: 25 g
carbohydrates, 18.2 g protein;
milk: 25 g carbohydrates, 18.2 g
protein; whey: 25 g carbohydrates,
18.2 g protein; cheese: 25 g
carbohydrates, 18.2 g protein
Treatments: glucose drink (25 g
glucose 250 ml water);
glucose drink lysine threonine;
glucose drink leucine, isoleucine
valin; glucose drink whey protein;
glucose drink leucine, isoleucine
valin lysine and threonine;
Treatments: 600 g of a liquid test
meal with 50 g tuna protein,
4.5 g fat, 11 g carbohydrates;
600 g of a liquid test meal with
50 g turkey protein, 4.5 g fat,
11 g carbohydrates; 600 g of a
liquid test meal with 50 g whey
protein, 4.5 g fat, 11 g carbohydrates;
600 g of a liquid test meal with 50 g
liquid egg albumin, 4.5 g fat, 11 g
carbohydrates
54 g of either whey protein isolate or
sodium caseinate application versus
control (glucose)
Glycemic index lowering peptide
fraction (GILP) mixture of whey
protein peptides and intact whey
protein: 0 g, 5 g, 10 g, 20 g GILP
added to a 50 g glucose drink
500 ml test solution (45 g whey protein)
with either whey protein isolate or
whey protein hydrolysate
Blood glucose, plasma insulin,
GLP-1, GIP, CCK-8
Fasting and postprandial plasma
concentrations of insulin,
glucose, glucagon, GLP-1, GIP
Blood glucose, serum insulin,
GLP-1, GIP
Blood glucose, serum insulin,
GIP, GLP-1-concentration
Plasma glucose and insulin
Plasma concentrations glucose
and insulin; HOMA-IR2
Blood glucose
Plasma concentration of glucose
and insulin, BCAA
For both, whey with premeal or
meal: insulin levels "; GIP
levels "; CCK levels "; blood
glucose levels #; iAUC for insulin,
GLP-1, GIP, CCK "; GLP-1 levels
"more when whey was provided
before the meal
iAUC for glucose # by whey meal;
no difference in insulin or
glucagon levels
Postprandial glucose responses
# with milk and whey; insulin
AUC " with whey; GIP AUCs
" with whey; GLP-1 AUCs were
not affected
Whey protein led to: blood glucose
response # with whey and
intervention 5; iAUC glucose #
with whey and intervention 3;
iAUC insulin # with whey and
intervention 3; iAUC for GIP "
with whey; GLP-1 levels did not
differ between interventions
Whey protein led to glucose iAUC #
compared to egg and turkey;
whey protein led to " iAUC
insulin compared to egg
Whey protein # plasma insulin;
insulin sensitivity " at week 12
#iAUC glucose in the 20 g GILP
intake study phase
Glucose # with both types of
whey protein intake; insulin "
with both types of whey protein
with tendency of higher peak
levels following whey protein
hydrolysate
(continued overleaf )
Effects of whey protein supplements on metabolism Graf et al. 573
 574 Functional foods

AUC, area under the curve; BCAAs, branched-chain amino acids; CCK, cholecystokinin; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HOMA, homeostasis model assessment; HOMA-IR2,
effect of protein type; GLP-1levels

compared to normal protein intake

wave analysis [32,34

], and two studies showed no

of insulin was " with high protein

compared to normal, no effect of

protein type; Ghrelin # with high
intake compared to normal, no
no effect of protein type; AUC
Significant effects of intervention

with high whey protein intake, effects [14,33].

protein intake without GMP

" with high protein intake
Peak glucose levels were #

The antihypertensive effect of whey protein is supposed

to result from an inhibitory effect of peptides derived

without GMP
from a-lactalbumin and b-lactoglobulin, the major whey
protein, on angiotensin-converting enzyme (ACE)
[35,36]. ACE inhibition prevents the conversion of angio-
tensin I to angiotensin II, a potent vasoconstrictor.
Several clinical studies have also shown an improvement
concentration, amino acid, urea
Plasma concentration of glucose,

in endothelial function in patients prescribed ACE

inhibitors [37], which could be the result of pleiotropic
insulin, ghrelin, GLP-1

effects of ACE inhibitors on the vascular endothelium

[38]. In addition, it is supposed that a-lactalbumin and
b-lactoglobulin have opioid-like activities and bind to
opioid receptors. Specific tetrapeptides derived from
Parameters

a-lactalbumin and b-lactoglobulin improved endothelial

vascular relaxation [39] and reduced BP of spontaneously
hypertensive rats [40,41]. These effects may be due to
opioids influence on the nitric oxide system [39]. Thus,
(protein as whey protein, high protein
protein content); 25/55/20 energy %

protein content); 25/55/20 energy %

whey protein may influence nitric oxide production

(protein/carbohydrate/fat) of either:
Application of a nutrient composition

glycomacropeptide (GMP), normal

(protein as whey protein without

(protein as whey protein without

10/55/35 energy % (protein as

which plays a role in BP regulation and endothelial

(protein as whey protein, high
content); 25/55/20 energy %

content); 10/55/35 energy %

whey protein, normal protein
Supplementation and duration

GMP, high protein content)

function [42]. Indeed, Ballard et al. [32] recently found

that acute ingestion of 5 g of a novel whey-derived pep-
tide (nitric oxide peptide, NOP-47), isolated from whey
protein hydrolysate, increased vascular endothelial func-
tion via mechanisms both dependent and independent of
nitric oxide production.

In addition, the effects of a regular whey protein supple-

mentation may be related to baseline BP, with those
individuals with higher baseline BP demonstrating
22 years, mean BMI 74.4 kg/m2
30 healthy individuals, mean age

greater reductions in BP in response to whey protein

treatment [13]. Whether the effects on BP and vascular
function are also dependent on the ingested whey dosage
has not been systematically examined in humans until
Individuals analyzed

now. However, based on the data of Pal and Ellis [34

] it

seems that higher doses of whey protein (54 g/day)
supplemented for more than 6 weeks may be required
to observe a measurable physiological effect. In contrast,
a one-off dose of whey protein isolate (45 g) was
inadequate to affect BP [9
].
square design; examination of acute
effects; four interventions separated
Randomized, single-blind, 2  2 Latin

homeostasis model assessment of insulin resistance.

Effects of whey protein on the musculoskeletal system

Regarding the effects on muscle metabolism many
reviews have been published in the past years concerning
by at least 1 week

the effect of protein and indispensable amino acids on

muscle hypertrophy during resistance training, with
Study design

special focus on whey and casein [43,44]. In brief, these

reviews showed that pre-exercise or postexercise inges-
tion of protein or indispensible amino acids can increase
MPS and result in a positive net protein balance, which
may be beneficial for promoting muscle hypertrophy [43].
et al. [28]

Following these reviews, four further recent studies

Reference

Veldhorst

have been published about the effect of whey protein

on muscle metabolism [12
,45,46
,47
] (Table 4).

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 Table 3 Randomized controlled intervention studies about the effects of whey protein on blood pressure and endothelial function
Reference Study design Individuals analyzed Supplementation and duration Assessment of vascular function Significant effects of intervention

Ballard et al. [32] Randomized, placebo-controlled, 20 healthy individuals, mean 5 g/day of NOP-47 or placebo, Baseline and postprandial NOP-47 " FMD (P < 0.0001 for
crossover, two treatments age 25 years, mean each treatment for 2 weeks (2-h test protocol) FMD, R-FBF, time  trial interaction) and
BMI 24.3 kg/m2 separated by a 2-week washout RH-FBF, plasma total nitrite/nitrate, RH-FBF (P 0.008 for time 
period TNFa, IL-6, IL-8, MCP-1, VEGF, trail interaction) compared to
sE-selectin, sVCAM-1, sICAM-1 baseline
at the end of the supplementation Total nitrites/nitrates # over the
periods 2 h postingestion and were
lower at 120 min after placebo
compared to NOP-47
Claessens Randomized, diet-controlled, 48 overweight and obese Energy restriction period (56 weeks), SBP, DBP No difference between the whey
et al. [14] single-blind, parallel, individuals, mean age weight maintenance (12 weeks): or casein-supplemented groups
four groups 45.4 years, mean BMI low-fat diet and maltodextrin
32.9 kg/m2 (high-carbohydrate group) or protein
(high-protein group): casein
(HPC subgroup) or whey (HPW
subgroup) supplements 2 25 g/day
Fluegel et al. [13] Randomized, controlled, parallel, 71 normotensive, prehypertensive, 28 g/day of either hydrolyzed whey protein SBP, DBP, MAP, pulse pressure Compared to control, hydrolyzed
two groups and stage 1 hypertensive concentrate or nonhydrolyzed whey measured at baseline and during whey protein did not affect BP
patients, mean age 20.6 years, protein concentrate (control) in the last day of weeks 2, 4, and 6; parameters
mean BMI 24.7 kg/m2 a fruit-flavored beverage; 6 weeks serum ACE activity at baseline and In patients with elevated DBP
week 6 and SBP, whey beverage
consumption # SBP, DBP, and
MAP by 8.0, 8.6, and 6.4 mmHg,
respectively compared to baseline;
in patients with elevated SBP only,
whey beverage consumption
# SBP by 3.8 mmHg compared
to baseline
Lee et al. [33] Randomized, placebo-controlled, 54 hypertensive patients, mean 125 ml of a milk drink supplement with SBP and DBP at week 0, 2, 4, 8, None
double-blind, parallel, two groups age 51.6 years, mean BMI whey peptides every morning or 12; 24-h ambulatory BP monitoring,
27.9 kg/m2 a control product for 12 weeks after IL-6, CRP, PAI-1 and number of
a run-in period of 2 weeks leukocytes at week 0 and 12
Pal and Randomized, controlled, 70 overweight and obese Supplement packages mixed with 250 ml Fasting SBP, DBP, AI (pulse wave SBP and DBP # at week 12 compared
Ellis [34

] single-blind, parallel, three groups individuals, mean age 48.3 years, water twice a day (breakfast, dinner): analysis), plasma IL-6, TNF-a and to baseline in whey and casein
mean BMI 31.3 kg/m2 27 g whey protein isolate or 27 g sodium CRP groups; DBP # in the whey and
caseinate or 27 g glucose (control); casein groups at week 12 compared
525 kJ/sachet; 12 weeks to control; AI # from baseline at
12 weeks in the whey group; AI
# in whey group at 12 weeks
compared to control and casein
Pal and Ellis [9
] Randomized, controlled, crossover, 20 overweight and obese 45 g whey protein isolate or 45 g sodium Fasting and postprandial: SBP, DBP, SBP, DBP, and AI # postprandial for
three treatments postmenopausal women, mean caseinate or 45 g glucose control mixed AI (pulse wave analysis), plasma IL-6, all treatments and returned to
age 57.5 years, mean BMI with water and consumed with TNF-a and CRP baseline values after 6 h; no
32.5 kg/m2 a breakfast meal; standardized evening significant differences in AI, SBP
meal before the intervention day, or DBP within or between the
6-h test period groups; no significant treatment
effects on plasma inflammatory
markers

ACE, angiotensin-converting enzyme; AI, augmentation index; CRP, C-reactive protein; DBP, diastolic blood pressure; FMD, brachial artery flow-mediated dilation; HDL, high-density lipoprotein; IL, interleukin; MAP, mean arterial
pressure; MCP-1, monocyte chemoattractant protein-1; PAI-1, plasminogen activator inhibitor-1; R-FBF, resting forearm blood flow; RH-FBF, reactive hyperemia forearm blood flow; SBP, systolic blood pressure; sE-selectin, soluble
endothelial-selectin; sICAM-1, soluble intracellular adhesion molecule-1; sVCAM-1, soluble vascular cell adhesion molecule-1; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.
Effects of whey protein supplements on metabolism Graf et al. 575

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 Table 4 Randomized controlled intervention studies about the effects of whey protein on musculoskeletal system
Reference Study design Individuals analyzed Supplementation and duration Bone and muscle health assessment Significant effects of intervention

Muscle
Burd et al. [46
] Randomized, parallel, 15 recreationally active men, 2 h prior to arrival on the morning of acute Muscle biopsy and blood samples to Regardless of condition rates of
576 Functional foods

three groups
Cooke et al. [45] Randomized, double-blind 17 untrained male participants,
placebo-controlled,
two groups
Pennings Randomized, parallel, 48 healthy older men, mean
et al. [12
] three groups
Reitelseder Randomized, single-blind, 17 healthy male individuals,
et al. [47
] parallel, three groups
Bone
Aoyagi et al. [56] Randomized, controlled, 79 elderly Japanese women,
parallel, two groups
mean age 21 years,
mean BMI 24.1 kg/m2
1.5 g/kg body weight of supplement
mean age 23 years, mean
body weight 80 kg
Standardized meal the evening before
age 74 years, mean
BMI 25.3 kg/m2
L-[1- C]leucine-labeled whey and
mean age 27 years,
mean BMI 23.5 kg/m2
Daily physical activity (step count and
mean age 72.5 years,
mean BMI 23.3 kg/m2
exercise a standardized liquid meal
(Ensure Plus); constant infusion of
13
L-[ring- C6] phenylalanine; protein
feeding at rest (15 g whey protein
isolate) and 24 h after resistance
exercise, unilateral leg exercise: four
sets at 90% of maximal
strength to failure (90FAIL), 30%
work-matched to 90FAIL (30WM)
or 30% to failure (30FAIL)
Cybex dynamometer for examining
per day; supplement: carbohydrate-only
or whey protein-carbohydrate (WPH)
(30 g consumed immediately, and
then once with breakfast, lunch, in the
afternoon and after the evening meal)
followed by a unilateral eccentric
contraction-based
resistance exercise session, consisting
of four sets of 10 repetitions at 120%
of maximum voluntary contraction one
leg press, leg extension and leg
flexion exercise machine, 14 days
Three muscle biopsies (t 0, 180, 360)
the experiment; Single bolus
(250 ml) containing 20 g intrinsically
13
L-[1- C] phenylalanine-labeled whey,
casein or casein hydrolysate,
continuous intravenous L-[1-13C]
phenylalanine infusion
13
Muscle biopsies and blood samples for
casein (0.3 g/kg lean body mass),
or a noncaloric control drink,
ingested immediately after exercise
Forearm bone mineral density (BMD),
duration of exercise >3 metabolic
equivalents for all, experimental and
control); experimental group: Milk
basic protein (MBP) supplementation
(40 mg/day) for 1 year
analyze muscle protein synthesis
muscle strength
FSR values " after whey than after
and plasma samples to analyze
postprandial mixed muscle fractional
synthetic rate (FSR)
analyzing myofibrillar protein synthesis
were taken before and after exercise
Calcaneal osteosonic index (OSI),
urinary deoxypyridinolin (Dpd); and
cross-linked N-telopeptid (NTx),
serum concentration of osteocalcin
(OC) and bone-specific alkaline
phosphatase (BALP)
mixed muscle protein and
sarcoplasmic protein synthesis
were similarly stimulated after
protein feeding at rest and
24 h after resistance training;
protein ingestion stimulated rates
of myofibrillar protein synthesis
above fasting rates and response
was enhanced 24 h after
resistance in the 90FAIL and
30FAIL conditions
Isometric knee extension strength
was " following WPH
supplementation 3 and 7 days
into recovery from exercise-
induced muscle damage; WPH
supplementation: knee extension
strength was greater after
7 days of recovery
casein and casein hydrolysate;
positive correlation between
peak plasma leucine
concentrations and postprandial
FSR values
Myofibrillar protein synthesis was
equally " 16 h postexercise
after whey and casein intake,
compared to control
No effect on OC or BALP
# Dpd and NTx in MBP-group
compared to controls after
1 year; " Dpd and NTx in control
group; MBP-group maintained
BMD and " OSI
Markers of bone resorption were
negatively correlated to measures
of physical activity after 1 year in
both groups

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 Effects of whey protein supplements on metabolism Graf et al. 577

the whole milk group after 6 months;

to baseline, no significant difference
Three of them suggest that resistance exercise followed

Total BMD " in all groups compared

MBP group after 8 months and in

BMD in all three groups; NTx # in
on the mean rate of gain of total
group; " OC in casein low/high

Serum-IGF " in both groups; zinc

by whey protein supplementation stimulates MPS

NTx between whole milk group

"OC in whey/low-mineral group;

after 1 week; CrossLaps # in

accelerated the IGF increase
[12
,46
,47
]; one study demonstrated that whey could

no significant differences in
# OC in whey/high mineral

zinc group after 1 week

abate exercise-induced damage after training with whey
supplementation [45].
mineral group

Whether whey or casein show a greater effect on promot-

and MBP
ing MPS seems to be controversial. Reitelseder et al.
[47
] demonstrated that whey protein and casein
immediately applied after resistance training result in
an overall equal MPS response, whereas Tang et al. [48]
Insulin-like growth factor (IGF), insulin-like

showed that acute effects of whey protein beat casein or

C-terminal telopeptide (CTX) and OC

L2L4 and the left forearm at 0 and

BMD of total body, lumbar vertebrae

soy protein in both conditions, at rest and after exercise.

8 months, serum NTx and BALP

Thereby, the stimulated MPS following the combination

Serum concentrations of BALP,

growth factor binding protein

of whey and resistance training seems to be effective in

at 0, 3, 6 and 8 months

both young and old individuals [12
,45,47
,49]. Although

(IGF-BP3); CrossLaps

most studies focussed on the acute effect of whey

supplementation, the few studies carried out on long-
term effects (14 days [45] to 21 weeks [43]) suggest that
whey protein could also lead to absolute gains in lean
body mass and strength [45,5053].

The possible effects of whey protein on bone health

10.5 g/day whey-protein; WLM/WHM

15 g whey protein 550 mg calcium)

have recently been examined in three studies: Two

540 ml/day of a milk drink (3 180 ml);

supplement daily for all; 30 mg/day

Protein (5 g essential amino acids
content); 42 g/day casein-protein;

Control, carton of 250 ml milk alone

studies investigated the effects of whey protein on bone

CLM/CHM (casein with low/high
(whey with low/high milk mineral

(whole milk) or with 40 mg MBP

of zinc or control (untreated);

metabolism [54,55], and one the effects of milk basic

milk mineral content): 7 days

every day in the same room,

protein (MBP) [56] (Table 4). Whey protein was com-

bined with either different levels of mineral intake [54]
or mere zinc and calcium supplementation [55]. In both
studies, the study design was unable to distinguish
8 months

between mere whey protein effects on bone metabolism

4 weeks

[54,55]. However, when only MBP was supplemented,

although the usually applied amount was rather small
(40 mg/day) [11,5662], positive effects on bone metab-
olism occurred. MBP contains approximately 98%
mean body weight 28.25 kg

52 hospitalized elderly, mean

81 young women, mean age

57 prepubertal Danish boys,

proteins, which are lactoferrin (54%), lactoperoxidase

age 85 years, mean BMI

19.6 years, mean BMI

(41%), other active, basic proteins and other milk

mean age 8.2 years,

proteins [59]. However, as summarized recently by Jesu-

dason and Clifton [11] MBP seems to decrease bone
23.3 kg/m2

20.4 kg/m2

resorption markers, increase bone formation markers and

increase bone mineral density (BMD). These effects of
MBP are also underlined by Aoyagi et al. [56] who
examined the effect of daily physical activity with or
without MBP supplementation (40 mg/day) on bone
Randomized, controlled,

Randomized, controlled,
double-blind, parallel,

double-blind, parallel,

Randomized, placebo-

metabolism in older women. After 1 year, excretion of

controlled, parallel,

bone resorption markers was lower in the MBP-supple-

three groups

three groups

mented group. The volunteers also maintained BMD

four groups

and had an increase of calcaneal osteosonic index

(1.5%) which suggests augmentation of bone health.
However, one might wonder, as Jesudason and Clifton
[11] also did, that the bone forming results of MBP are
only described by one group and mainly in a Japanese
Mark et al. [54]

Zou et al. [57]

population. In this respect it should be noted that the

et al. [55]
Rodondi

Japanese have a different genotype than whites, leading

to a higher bone mass and lower bone turnover in
Japanese [63].

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 578 Functional foods
Discussion
Summarizing the results of whey protein on metabolic
disorders, cardiometabolic risk factors, and the muscu-
loskeletal system, a number of human trials describe
beneficial physiological effects, and in some publications
whey protein is even recommended in the development
of functional foods. However, the mechanisms by which
whey protein is effective are multiple and are in detail not
well understood.
With respect to the effects of whey on glucose metab-
olism, it has been demonstrated that whey protein leads
to higher levels in incretins like GLP-1 [25,28] and GIP
[25] or functions as an aminopeptidase dipeptidyl pepti-
dase-4 (DPP 4) inhibitor [64,65]. All these may reduce
postprandial blood glucose levels. Additionally, whey
protein also has a b-cell-stimulating effect which seems
to be mainly addressed to the high content of BCAAs.
However, whey protein as well as casein also does contain
glutamine. Glutamine by itself has an incretin-stimu-
latory, but also a glucose-ameliorating effect. The latter
may be related to a specific glutamine effect on fat
metabolism [66].
The observed BP-lowering effect of whey protein might
be caused by the inhibition of ACE, a key component of
the renin-angiotensin-aldosterone system (RAAS). ACE
inhibition also leads to decreased adipocyte size and
increased adiponectin levels which by itself leads to
increased insulin sensitivity [67]. Additionally, renin-
angiotensin system blockade was recently shown to
enhance islet blood flow, oxygen tension, and insulin
biosynthesis, thus improving b-cell function and glucose
tolerance [68].
It should, however, be noted that in the human trials in
which plasma RAAS parameters (e.g. ACE activity) were
measured during the intake of whey protein, no evidence
for an in-vivo ACE inhibition was found [13]. In addition,
it is unclear whether the oral intake of whey protein can
result in an effective blood concentration of bioactive
whey compounds that approach that of pharmacological
ACE inhibitors. More research is therefore needed on the
regulatory mechanisms other than the RAAS to scrutinize
whether BP or insulin resistance can be reduced by whey
protein supplementation.
In summary, the currently published data although
quite positive are not sufficient to make any final
recommendation with respect to a specific whey protein
dosage. However, most of the studies which showed
beneficial physiological effects have been carried out
with 2025 g and/or daily supplementation of more than
50 g of whey protein. Even though, to achieve such
amounts within a habitual diet seems to be unrealistic.
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Obviously, dependent on the outcome parameter differ-
ent study designs are mandatory. For glucose metabolism
or MPS even a bolus application led to beneficial effects,
however, further long-term studies are mandatory to
verify the respective effect. On the contrary, regarding
vascular function, more studies examining both acute and
long-term effects are needed to derive specific recom-
mendations.
The whey protein-induced reduction in BP of approxi-
mately 58 mmHg [13,34

] is similar to the effects of
other recommended dietary and lifestyle approaches
to prevent and treat hypertension, such as body
weight reduction in overweight/obese individuals,
sodium reduction, or increased physical activity [69].
Regarding the clinical relevance of whey protein supple-
mentation in the context of blood glucose control,
Ma et al. [25] demonstrated that 55 g decreased blood
glucose in similar ranges as the application of sulfony-
lureas [70].
Conclusion
Supplementation with whey protein might have a poten-
tial to improve glucose metabolism and MPS. However,
further research in particular in risk populations is needed
such as individuals with T2DM, metabolic syndrome and
the elderly. These studies should focus on both acute and
long-term effects of whey protein ingestion. In addition,
further research investigating the mechanisms of whey
protein effects is recommended.
(1) Whey protein appears to have a blood glucose and/or
insulin-lowering effect.
(2) Whey protein may increase MPS.
(3) No clear-cut effects have been shown on blood lipids
and lipoproteins, BP and vascular function.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest


of outstanding interest
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