R E V I E W Open Access
Dietary whey protein lessens several risk factors
for metabolic diseases: a review
Gabriela TD Sousa
, Fábio S Lira
, José C Rosa
, Erick P de Oliveira
, Lila M Oyama
, Ronaldo V Santos
Gustavo D Pimentel
Obesity and type 2 diabetes mellitus (DM) have grown in prevalence around the world, and recently, related
diseases have been considered epidemic. Given the high cost of treatment of obesity/DM-associated diseases,
strategies such as dietary manipulation have been widely studied; among them, the whey protein diet has reached
popularity because it has been suggested as a strategy for the prevention and treatment of obesity and DM in
both humans and animals. Among its main actions, the following activities stand out: reduction of serum glucose
in healthy individuals, impaired glucose tolerance in DM and obese patients; reduction in body weight;
maintenance of muscle mass; increases in the release of anorectic hormones such as cholecystokinin, leptin, and
glucagon like-peptide 1 (GLP-1); and a decrease in the orexigenic hormone ghrelin. Furthermore, studies have
shown that whey protein can also lead to reductions in blood pressure, inflammation, and oxidative stress.
Keywords: Whey protein, Obesity, Type 2 diabetes mellitus, Appetite, Inflammation, Hypertension.
Excess bodyweight in humans has been increasing
worldwide. It is considered an epidemic by the World
Health Organization (WHO) [1,2]. Recently, it was esti-
mated that more than 300 million people worldwide are
obese and more than 1 billion are overweight .
Similar to obesity, type 2 diabetes mellitus (DM) has
been regarded as a major global epidemic of the 21
century . In addition, obese individuals twice as likely
to develop metabolic syndrome (MS) comorbidities .
Obesity and DM are MS-associated diseases. Although
the pathogenesis of MS and each of its components is
complex and poorly understood, abdominal obesity and
insulin resistance are recognized as risk factors for MS.
Furthermore, patients with MS have a five-fold higher
risk of developing DM .
Patients with DM have an elevated response to post-
prandial triacylglycerols compared to non-diabetic sub-
jects. Additionally, postprandial triacylglycerols are also
known to be strongly associated with cardiovascular
Reductions in body weight can reduce obesity-related
problems [8-10]. Accordingly, dietary manipulations may
promote increased satiety, to stimulate the anorexigenic
hormones and consequent to reduce food intake and
body weight . Therefore, is extremely important to
discover strategies that maximize the effect of weight
loss and inhibit weight regain after short- and long-term
of nutritional counseling [2,12,13]. Likewise, diet supple-
mentation with milk serum protein has been suggested
as an adjunct strategy in the prevention and treatment
of obesity and MS-related diseases in humans [14,15]
and animals [16,17]. In addition, dietary milk serum pro-
teins, e.g., whey protein, have high nutritional value
because it contains all essential amino acids in higher
concentrations than vegetable protein sources [18,19].
Based on that, this review aims to discuss the main
effects of whey protein in the treatment or prevention of
obesity, DM, hypertension, oxidative stress and MS-
linked metabolic complications.
For the preparation of this review, we performed biblio-
graphic searches in databases of the CAPES Periodic
* Correspondence: firstname.lastname@example.org
Departamento de Clínica Médica, Universidade Estadual de Campinas
(UNICAMP), Campinas/SP, MA: 13083-970, Brazil
Full list of author information is available at the end of the article
© 2012 Souza et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Sousa et al. Lipids in Health and Disease 2012, 11:67
Portal, Scielo, and Medline/Pubmed, covering articles
published between 2003 and 2012. A search of articles
was made using the key words “whey protein,”“milk
serum protein,”“type 2 diabetes mellitus,”“obesity,”
“metabolic syndrome,”and “protein hydrolysates.”
Main nutritional and functional components of whey
Milk serum proteins are defined as substances that
remain soluble in milk serum . These proteins are
naturally formed during the production of cheese [19,21]
and account for 20% of the all protein in milk [21-23],
such as β-lactoglobulins, α-lactalbumin, immunoglobu-
lins, lactoferrin, lactoperoxidase, glycomacropeptide,
bovine serum albumin [18,20,22,24], and other proteins
In addition, whey protein has high concentrations of
branched chain amino acids (BCAAs), such as leucine,
isoleucine, and valine, which are also related to import-
ant factors for muscle growth, build, and repair [14,25].
Milk serum proteins do not coagulate in acidic condi-
tions; they resist the action of quimosine from the stom-
ach, quickly reach the jejunum , are rapidly digested,
and raise plasma amino acid concentrations of [21,26].
Therefore, milk serum proteins perform several func-
tions, such as mineral absorption, improvement of pro-
tein synthesis, sensitivity to hormones, and decreased
blood glucose and lipid levels [7,15,16,21,23,27-29]. In
summary, the main nutritional and functional compo-
nents of whey protein are presented in Table 1.
Improvement risk factors for metabolic diseases
Several types of diets are being studied to find a model
that has the quality and quantity of nutrients to promote
weight loss, reduction of body fat, maintenance of
muscle mass and satiety control [10,13,14,29,35-37].
Frestedt et al.  demonstrated that the supplemen-
tation with a mixture of whey protein isolate with other
peptides (2 servings/day and each serving with 10 g pro-
tein) for 54 healthy subjects for 12 weeks, in addition to
47 control subjects who consumed glucose (10 g/serv-
ing) led to weight loss in both groups, but the group
supplemented with whey protein had higher weight loss.
They also had greater reductions of body fat (6.1%) and
a higher maintenance of lean mass than the control
group who had consumed just glucose.
Pilvi et al.  studied mice that had diet-induced
obesity and were subsequently fed a low-calorie diet with
different types of proteins (whey protein isolate, α-lactal-
bumin, β-lactoglobulin, and lactoferrin) for 50 days, and
after this period, they returned to high fat diet. The mice
that consumed α-lactalbumin (45.9 g) had a significant
loss of fat mass during the caloric restriction period and
a reduction in visceral fat during the weight recovery
period when compared to other groups. But this is not a
conclusive explanation about the mechanisms that lead
to such results.
Another component of milk, calcium, has been exten-
sively studied with a possible anti-obesity role. But Pilvi
et al.  observed a significant decrease in weight gain
and body fat and a higher fat excretion in mice fed for
21 weeks with high-fat diet (60% of total calories from
fat), 18% protein (whey protein isolate), and 1.8% cal-
cium carbonate (CaCO
) in comparison with a similar
diet that had casein as the protein source. The authors
suggest that a possible explanation for this result is the
high levels of leucine present in the whey protein, e.g.,
the leucine may modulate insulin signaling by phospha-
tidylinositol 3 kinase (PI3K) directing the energy to
muscle synthesis and not for storage in adipose tissue.
Table 1 Main components and actions of whey protein
Has content higher of branched chain amino acids (~25.1%). Capture
hydrophobic molecules, participating in the reduction of intestinal
absorption of lipids.
Has content higher of tryptophan (6%) of all dietary proteins. It is rich
in lysine, leucine, threonine, and cysteine. It has the ability to bind to
minerals such as Ca and Zn, positively affecting their absorption.
Four classes of immunoglobulins are present in serum: IgG, IgA, IgM,
and IgE. It functions as an antioxidant protection and increases immunity.
Lactoferrin (~1%) Inhibits the production of pro-inflammatory cytokines and protects
against the development of hepatitis.
Lactoperoxidase (<1%) Important antimicrobial properties
Glicomacropeptide (10–15%) It is formed from the digestion of κ-casein during coagulation of
cheese. It is high in essential amino acids that favor the absorption of
Bovine serum albumin Good profile amino acid and function of binding to lipids.
Muro Urista et al. , Graf et al. , Gilbert et al. , Dougkas et al. , Madureira et al. .
Sousa et al. Lipids in Health and Disease 2012, 11:67 Page 2 of 9
Subsequently, Pilvi et al.  showed that mice that con-
sumed a high-fat diet (60% of total calories from fat)
with 18% protein (whey protein isolate) and 1.8% cal-
cium carbonate for 12 weeks had not only an inhibition
in the accumulation of fat mass but also an increase in
gene expression in the visceral adipose tissue of leptin
and β3-adrenergic receptor when compared to another
group of mice that received a diet with similar fat and
protein contents, that instead used casein instead of
whey and only 0.4% calcium carbonate. Thus, the
authors suggest that the whey protein isolate may reduce
obesity via improvement of leptin sensibility.
Baer et al.  showed that the type of protein can in-
fluence the weight loss response. Supplementation with
56 g of whey protein (consumed twice daily) for 23 weeks
diminished body weight and fat mass when compared
with the group that consumed just carbohydrates. More-
over, waist circumference and fasting ghrelin levels were
lower in the whey protein group when compared to the
group that ingested soy protein. These results demon-
strated that through yet-unknown mechanisms, different
sources of dietary protein may differentially facilitate
weight loss and affect body composition.
In addition to the type dietary of protein, the propor-
tion of nutrients also influences energy consumption
and body composition . Pichon et al.  observed a
reduction in body weight and adipose tissue in rats after
25 days of consuming a high-protein diet (55% of total
energy intake) compared to rats that consumed a normal
protein diet (14% of energy). In addition, the results
were more pronounced with the high protein diet con-
taining whey protein isolate enriched with β-lactoglobu-
lin compared with other protein sources, such as whole
milk and whey protein concentrate. The authors sug-
gested that these results were obtained because the pro-
teins have a greater power of satiety when compared to
the other nutrients. Moreover, β-lactoglobulin may cap-
ture hydrophobic molecules, decreasing the absorption
of fat by intestinal cells. Furthermore, a high protein diet
induces to increases in thermogenesis .
Furthermore, the reduction of body weight and body
fat  and the decrease of serum triacylglycerols levels
in obese individuals are extremely important, since these
individuals are at increased risk for cardiovascular dis-
eases [23,26]. Recently, Mortensen et al.  showed a
decrease in triacylglycerol levels when whey protein was
supplemented in DM patients. In addition, Pal et al. 
confirmed these results in both overweight and obese
post-menopausal women. This reduction was found after
consumption of 45 g of whey protein isolate together
with a high-fat meal when compared to consumption of
the equivalent amount of glucose or casein. Pal et al.
 also showed a decrease in triacylglycerol concentra-
tion in both overweight and obese individuals after
12 weeks of supplementation with 54 g of whey protein
compared to control group (without supplementation)
and with consumption of the same amount of glucose.
As a reduction of ~20% in serum triacylglycerols has
been shown to reduce the progression of coronary dis-
eases, these results are very important to decreasing
Kasim-Karakas et al.  studied the influence of the
ingestion of whey protein in overweight and obese
women with polycystic ovary syndrome (PCOS). It has
been known that a reduction in body weight improves
the symptoms of PCOS. Accordingly, the intake of 75 g
of whey protein isolate compared to 75 g of glucose
reduced the ghrelin levels for 5 hours after consumption.
Therefore, these results also suggest that the whey pro-
tein can prolong satiety.
Recently, Pal and Ellis  showed in overweight and
obese individuals that supplementation of whey protein
(54 g) for 12 weeks did not significantly reduce the body
weight, BMI, waist circumference, and total body fat, but
decreases the triacylglycerol and insulin levels after
Collectively, these studies that relationship whey pro-
tein and obesity showed improvement in insulin sensitiv-
ity and lipid profile with possible increase of energy
Type 2 diabetes mellitus
Although insulin is a hormone anorectic [42-45] and
suppresses ghrelin , it is also an anabolic hormone
and therefore is related to increases in muscle protein
synthesis . Furthermore, hyperinsulinemia inhibits
hormone sensitive lipase (HSL), suppressing the release
of fatty acids from adipose tissue  and stimulates the
lipoprotein lipase (LPL) and fatty acid synthesis, contrib-
uting to obesity . However, the increase in insulin
levels after consumption of whey protein reported in
several studies is not able to promote the increase of fat
mass, perhaps due to the high leucine contents present
in whey protein and also because its consumption over
the long-term (>12 weeks) improves insulin sensitivity
Recent studies have shown the important role of whey
protein supplementation in glycemia control, possibly
through the stimulation of incretin hormones, which in-
crease fasting and postprandial insulin release and im-
prove insulin sensitivity [41,46-48].
Pichon et al.  showed that a high-protein diet
raises insulin concentrations compared to a normopro-
teic diet. However, in human and rat studies in which
the protein is combined with carbohydrate, an increase
in the insulin response has been observed [14-16]. In
addition, whey protein stimulates insulin secretion, and
when compared to casein, milk serum proteins have
Sousa et al. Lipids in Health and Disease 2012, 11:67 Page 3 of 9
increased postprandial insulinotropic effects that are
probably mediated by the rapid serum absorption of
BCAAs, the improvement in glucose homeostasis in
DM, and the possible delay or withdraw of the medicine
Recently, Gunnarsson et al.  showed the effects of
acute administration of whey protein plus glucose by
nasogastric tube (enteral diet) in mice when compared
to the administration of only glucose. In this study, the
authors found an increase in insulin levels three times
greater and an insulin tolerance four times greater with
consumption of whey protein.
Petersen et al.  observed in healthy subjects a sig-
nificant reduction in postprandial glucose (37.5%) when
consumed in a single dose containing 50 g of carbohy-
drate plus milk serum proteins (20 g in total). This de-
crease was dose-dependent; thus, the higher the protein
intake, the greater its effect on blood glucose. The same
effect was observed by Frid et al.  in DM subjects
that consumed milk serum protein. In this study, the
authors found a significant increase in insulin and glu-
cose-dependent insulinotropic peptide (GIP).
Recently, Mortensen et al.  confirmed the
hypoglycemic effect of whey protein in individuals with
DM within eight hours of consuming a meal test that
contained 45 g of whey protein compared to three other
meals containing different protein sources, casein, glu-
ten, and codfish. Moreover, within six hours of a meal
test a reduction in triacylglycerol concentrations was
observed with the supplementation of whey compared
to three other meals that contained a different type of
protein. Interestingly, all protein meals were associated
with a high-fat diet (100 g of butter).
Lan-Pidhainy and Wolever  also observed a signifi-
cant hypoglycemic effect in individuals with insulin re-
sistance after the consumption of a drink containing
30 g of whey protein plus 50 g of glucose compared to
groups of individuals who consumed only 50 g glucose
or another group who consumed 50 g of glucose plus
30 g of canola oil.
Studies performed in rats [16,17] showed that supple-
mentation with whey protein possibly suppressed serum
glucose level by the inhibition of the enzyme dipeptidyl
peptidase-IV (DPP-IV), whose function is to disable the
incretin hormones, such as GLP-1 (glucagon-like peptide
1) and GIP, which are both related to glycemic control.
Gunnarsson et al.  suggest, in mice, that the diges-
tion of whey protein leads to the formation of di- and
tri-peptides that are a substrate for DPP-IV. Neverthe-
less, Frid et al.  and Mortensen et al.  found no
changes in blood GLP-1 levels, only decreased glucose
levels after consumption of different amounts, 36.4 g
and 45 g of whey protein in DM individuals. These find-
ings may possibly occur because, in diabetic subjects,
the secretion postprandial GLP-1 is decreased [15,49]
and the enzyme activity DDP-IV is increased .
In healthy individuals, an increased GLP-1 levels due
to consumption of whey protein is more palatable .
Recently, Veldhorst et al.  observed an increase in
blood insulin (91%) and GLP-1 (164%) levels after con-
sumption of a diet containing 25% of calories from pro-
tein (whey protein), 55% from carbohydrates, and 20%
from lipids compared to similar quantities of casein. In
addition, non-significant reduction of blood glucose with
the consumption of whey compared to casein was
In summary, protein is important in fetal growth and
development of the pancreas. Furthermore, adaptations
to nutritional stress may permanently alter the physi-
ology and metabolism of several organs, leading to long-
term diseases such as cardiovascular diseases, DM, and
MS . Likewise, Barnett et al.  observed reduction
of 55–65% in insulin secretion in adult life in the off-
spring of mother rats who consumed low amounts of
protein (whey protein) during pregnancy. This reduction
is related to the early development of DM in adult
Therefore, whey protein may be utilized by reduce in-
sulin resistance due the increase in secretion of GLP-1
and to reduce serum glucose and insulin levels.
Hypertension is commonly found in patients with DM
and may affect approximately 60% of Brazilian indivi-
Recently, it was discovered that diet is a major deter-
minant of blood pressure. Likewise, certain foods have a
direct role in the reduction of blood pressure or add-
itional reductions in cardiovascular mortality [41,53].
Some amino acids of the whey protein, e.g., α-lactalbu-
min and β-lactoglobulin, are precursors of peptide inhi-
bitors of angiotensin-converting enzyme (ACE) .
ACE is a key enzyme in the regulation of blood pressure
Pal and Ellis  showed the hypotensive effect that
occurs after intake of whey protein (54 g protein) and
casein (27 g protein) in either obese or overweight
normotensive individuals. However, the components of
proteins that could possibly lead to the improvement of
blood pressure were not analyzed in this study. Likewise,
Lee et al.  found no decrease in blood pressure in
individuals with mild hypertension who consumed a
drink containing skim milk with milk serum proteins
(125 mL) for 12 weeks. The low level of peptides (2.6 g
per 100 g of protein drink) administered together with
protein may have been responsible for the absence of an
effect on blood pressure.
Sousa et al. Lipids in Health and Disease 2012, 11:67 Page 4 of 9
In summary, whey protein is associated with reduction
blood pressure by inhibition of ACE enzyme and pos-
sibly via lower body weight gain in individuals that
habitually consumed the aminoacids from whey protein
or BCAA than those subjects that consumption others
aminoacids, for e.g. non essential. Therefore, whey pro-
tein can in the future be considered extremely important
for the control of hypertension.
Possible mechanisms involved in reducing risk factors for
Reduction of food intake
Satiety is an important factor in the regulation of food
intake and also in the control of obesity [11,45]. Dietary
protein and specific amino acids are involved in the con-
trol of gastric and intestinal motility and in pancreatic
secretion, and are more potent in inducing satiety than
carbohydrates or fats .
Gut peptides that regulate the digestive process and
neuronal signaling in the central nervous system (CNS)
regulate hunger and satiety . Table 2 lists several
peripheral hormones and their roles in the regulation of
food intake .
Milk serum proteins are more potent stimulants of
cholecystokinin (CCK) and GLP-1 than casein
[26,41,51]. Among the peptides involved with whey pro-
tein, glycomacropeptide is an effective secretagogue of
CCK . CCK is a hormone secreted by I cells of the
small intestine that has as one of its functions to modu-
late satiety . However, Burton-Freeman  did not
observe the effect of dietary whey protein on the
increase of postprandial CCK levels in healthy subjects.
Therefore, we may to infer that probably a dose of whey
was insufficient to stimulate the CCK.
Pal and Ellis  observed a significant decrease in
glucose, appetite, and food intake, and an increase in
serum insulin levels after the consumption of a drink
containing 50 g of whey protein when compared to the
consumption of a similar amount of protein tuna, tur-
key, or egg albumin. This study suggests a potential
application of these foods in appetite control in both
overweight and obese individuals.
Furthermore, other amino acids not described in this
review are also associated with satiety, such as tryptophan,
which is a precursor of serotonin and an important modu-
lator of appetite .
Although the gut hormones are known by increase of
anorexigenic hormones, also was observed that the leu-
cine when injected directly in the central nervous system
reduces the food intake and body weight . Further-
more, Ropelle et al.  found that both leucine intra-
cerebroventricular injection or high-protein diet
decrease AMPK and increase mTOR phosphorylation in
the CNS inhibiting the neuropeptide Y and stimulating
the pro-opiomelanocortin expression, leading to reduc-
tion of food intake.
In summary, these findings suggesting that the aminoa-
cids from whey protein may reduce the food intake via in-
crease of gut hormones (CCK and GLP-1), and reduction
of neuropeptide orexigenic (NPY) and increase of neuro-
peptide anorexigenic (POMC) in the hypothalamus.
Adipose tissue is an endocrine organ that releases hor-
mones, cytokines, and others substances that tend to im-
pair insulin sensitivity . Obese individuals have
increased secretion of adipocytokines by adipose tissue
and macrophages .
Recently, Pal & Ellis  observed in overweight and
obese subjects that the supplementation of whey protein
(54 g) for 12 weeks did not change the pro-inflammatory
markers (IL-6, C-reactive protein-CRP, and TNF-α).
However, in D-galactosamine-induced hepatitis and liver
fibrosis in rats, the consumption of whey protein
strongly reduced the plasma levels of pro-inflammatory
cytokines (IL-1 beta: 59% and IL-6: 29%) compared to
the consumption of the same amount of casein .
Collectively, reduction of pro-inflammatory cytokines
may be associated with reduction of body weight gain
after consumption of whey protein and it aminoacids.
Anti-oxidative stress actions
Oxidative stress has been associated with MS, which is a
disease recognized by inflammatory effects that are
linked with the activation of reactive oxygen species
(ROS) [63-65]. Nowadays, indicators that are more
Table 2 Characteristics and functions of hormones
related to appetite regulation
Hormones Production and effects
CCK Produced: duodenum
Effect: reduces appetite
GLP-1 Produced: mainly in distal intestine (L cells)
Effect: reduces appetite
Ghrelin Produced: stomach
Effect: stimulates appetite
GIP Produced: K cells of the duodenum
Effect: reduces appetite and potentiate insulin release
Leptin Produced: mainly in adipose tissue
Effect: suppress appetite
Uroguanylin  Produced: intestinal epithelial cells
Effect: reduces appetite
CCK: cholecystokinin, GLP-1: glucagon-like peptide 1, GIP: glucose-dependent
insulinotropic peptide. Adapted: Pimentel & Zemdegs, 2010  and Pimentel
et al. .
Sousa et al. Lipids in Health and Disease 2012, 11:67 Page 5 of 9
typically used in the evaluation of ROS are the endogen-
ous antioxidant enzymes such as glutathione peroxidase,
catalase, and superoxide dismutase, and other compo-
nents such as malondialdehyde (MDA) and thiobarbitu-
ric acid reactive substances (TBARS) [63-66]. Recently,
the administration of 100 mg/kg of body weight of whey
protein in streptozotocin-induced diabetic rats was
found to decrease several oxidative stress indicators,
such as MDA, nitric oxide, and ROS concentrations; as
well as reduction of pro-inflammatory cytokines (IL-1β,
TNF-α, IL-6 and IL-4) and increase glutathione levels
. Another study observed that rats fed high-carbohy-
drate, fat-free diets to induce fatty livers (nonalcoholic
fatty liver model) plus orally administered whey protein
(0.15 g/d/rat) for 28 days reduced MDA and increased
glutathione levels .
Haraguchi et al.  found a protective effect against
oxidative stress, mainly in the liver, and a beneficial ef-
fect on renal function in rats supplemented with whey
protein plus a hypercholesterolemic diet, but they did
not observe a reduction in serum cholesterol levels.
In human studies, beneficial effects in the reduction of
oxidative stress after treatment with whey protein [69-
71]. Likewise, supplementation with 20 g/d of whey pro-
tein isolate for 12 weeks in subjects with nonalcoholic
steatohepatitis was found to increase the glutathione and
total antioxidant capacities . In healthy individuals,
45 g/day of whey protein supplementation in bar format
for 14 days also increased lymphocyte glutathione levels
. De Aguilar-Nascimento et al.  studied patients
with ischemic stroke that were fed via a nasogastric tube
a diet with 35 kcal/kg/d and 1.2 g of protein/kg/d con-
taining whey protein and an observed reduction in IL-6
and an increase in glutathione levels after five days of
Furthermore, several studies also shown in different
models of oxidative stress that only whey protein or
diets that contain this protein improve antioxidant func-
tion and decrease oxidative stress [72-75].
Collectively, these findings suggest that whey protein
may act as a nutritional component to increase endogen-
ous antioxidant enzymes (glutathione peroxidase, cata-
lase, and superoxide dismutase) and to reduce oxidative
stress markers (MDA, TBARS) jointly with low expres-
sion of pro-inflammatory cytokines (IL-1β, IL-6 and
TNF-α) in obese, diabetic or stroke patients.
Commercialization and safety doses of whey protein
Whey protein can be found in drinks, powder, protein
bars, and milk. The main natural source of whey protein
is bovine milk that has approximately 3.5% protein, of
which 80% is casein and the remaining 20% is whey pro-
tein [22,76]. Whey protein concentrate also may include
29–89% milk serum protein, and isolates should contain
more than 90% whey protein . In addition, whey pro-
tein can also be found in the form of hydrolysates. This
form of whey protein hydrolysates aims to optimize the
physical, chemical, and nutritional properties, improving
the absorption of proteins .
According to the studies presented in this review, the
amount of whey protein administered to adult humans
is between 5.0–54.0 g at durations of approximately
12 weeks. Furthermore, no serious adverse effects were
observed with whey protein supplementation. However,
this supplementation must make part of a habitual diet.
This review shows that whey protein may improve sev-
eral risk factors for DM, obesity, hypertension, oxidative
stress and MS (Figure 1). In addition, new studies
Figure 1 Main mechanisms of action of whey protein in protection of risk factors for metabolic diseases, such as obesity, type 2
diabetes mellitus, hypertension, oxidative stress and metabolic syndrome.
Sousa et al. Lipids in Health and Disease 2012, 11:67 Page 6 of 9
suggest a relationship between consumption of whey
protein source foods and oxidative stress, hepatoprotec-
tive effects, and increased resting energy expenditure.
Kume et al.  demonstrated a hepatoprotective effect
of consumption of whey protein D-galactosamine-induced
hepatitis and liver fibrosis in rats. There was a significant
decrease in the activity of hepatic enzymes (AST: 92.5%,
ALT: 98%, LDH: 65%, hyaluronic acid: 60%) after con-
sumption of whey protein compared to casein.
In trained subjects, Hackney et al.  observed a sig-
nificant increase (5%) after 24 hours of resting energy
expenditure with the consumption of 18 g of whey pro-
tein before of a single session of resistance training (70–
75% of one repetition maximum) when compared to an
intake of 19 g of carbohydrates. The authors speculate
that this increase occurred by the increased availability
of amino acids to skeletal muscle after whey protein in-
take. In addition, there was a decrease in respiratory
coefficients in both the consumption of carbohydrates
(5%) and whey (6%); this reduction indicates the
increased oxidation of fat. Furthermore, more studies
are needed to determine whether supplementation of
whey protein plus a balanced diet and resistance training
can increase the long-term increase in resting energy ex-
penditure and improve body composition.
In summary, whey protein has an attractive effect on glu-
cose metabolism control in healthy, overweight, obese,
and insulin-resistant subjects. Moreover, whey protein
assures a higher satiety; this effect is involved with the
modulation of several gut hormones related to the reduc-
tion of food intake, with increased release of anorectic
hormones, such as cholecystokinin, leptin, and GLP-1 and
decreased release of the orexigenic hormone, ghrelin; and
reduction of neuropeptide Y and increase of pro-opiome-
lanocortin in CNS. In addition, the reductions of expres-
sion of both inflammatory and oxidative stress markers, as
well as the reduction in blood pressure, are also the main
beneficial of risk factors for metabolic diseases.
The authors declare that they have no competing interests.
We would like to thank funding from the FAPESP.
Departamento de Fisiologia e Biofísica, Instituto de Ciências Biomédicas,
Universidade de São Paulo (USP), São Paulo/SP, Brazil.
Bioquímica e Fisiologia do Exercício, Universidade do Extremo Sul
Catarinense, Criciúma/SC, Brazil.
Departamento de Patologia, Universidade
Estadual Paulista (UNESP), Botucatu/SP, Brazil.
Departamento de Fisiologia,
Universidade Federal de São Paulo (UNIFESP), São Paulo/SP, Brazil.
Departamento de Psicobiologia, Universidade Federal de São Paulo
(UNIFESP), São Paulo/SP, Brazil.
Departamento de Clínica Médica,
Universidade Estadual de Campinas (UNICAMP), Campinas/SP, MA: 13083-
GDP was the responsible by design of whole manuscript, GTDS and GDP
wrote the paper, FSL, JCR, EPO, LMO, and RVS participated of choose and
discussion of papers included . All authors read and approved the final
Received: 14 February 2012 Accepted: 7 June 2012
Published: 7 June 2012
1. Giskes K, van Lenthe F, Avendano-Pabon M, Brug J: A systematic review of
environmental factors and obesogenic dietary intakes among adults: are
we getting closer to understanding obesogenic environments? Obes Rev
2. Pimentel GD, Arimura ST, de Moura BM, Silva ME, de Sousa MV: Short-term
nutritional counseling reduces body mass index, waist circumference,
triceps skinfold and triglycerides in women with metabolic syndrome.
Diabetol Metab Syndr 2010, 2:13.
3. WHO: Global strategy on diet, physical activity and health: obesity and
overweight. Geneva: World Health Organization; 2012. http://www.who.int/
4. Misra A, Khurana L: Obesity-related non-communicable diseases: South
Asians vs White Caucasians. Int J Obes (Lond) 2011, 35:167–187.
5. Gigante DP, Moura EC, Sardinha LM: Prevalence of overweight and
obesity and associated factors, Brazil, 2006. Rev Saude Publica 2009, 43
6. Rodrigues TC, Canani LH, Gross JL: Metabolic syndrome, insulin resistance
and cardiovascular disease in type-1 diabetes mellitus. Arq Bras Cardiol
7. Mortensen LS, Hartvigsen ML, Brader LJ, Astrup A, Schrezenmeir J, Holst JJ,
Thomsen C, Hermansen K: Differential effects of protein quality on
postprandial lipemia in response to a fat-rich meal in type 2 diabetes:
comparison of whey, casein, gluten, and cod protein. Am J Clin Nutr 2009,
8. de Oliveira EP, Manda RM, Torezan GA, Corrente JE, Burini RC: Dietary,
anthropometric, and biochemical determinants of plasma high-density
lipoprotein-cholesterol in free-living adults. Cholesterol 2011,
9. Takahashi MM, de Oliveira EP, Moreto F, Portero-McLellan KC, Burini RC:
Association of dyslipidemia with intakes of fruit and vegetables and the
body fat content of adults clinically selected for a lifestyle modification
program. Arch Latinoam Nutr 2010, 60:148–154.
10. Frestedt JL, Zenk JL, Kuskowski MA, Ward LS, Bastian ED: A whey-protein
supplement increases fat loss and spares lean muscle in obese subjects:
a randomized human clinical study. Nutr Metab (Lond) 2008, 5:8.
11. Solah VA, Kerr DA, Adikara CD, Meng X, Binns CW, Zhu K, Devine A, Prince
RL: Differences in satiety effects of alginate- and whey protein-based
foods. Appetite 2010, 54:485–491.
12. Pimentel GD, Portero-McLellan KC, de Oliveira EP, Spada AP, Oshiiwa M,
Zemdegs JC, Barbalho SM: Long-term nutrition education reduces several
risk factors for type 2 diabetes mellitus in Brazilians with impaired
glucose tolerance. Nutr Res 2010, 30:186–190.
13. Pilvi TK, Harala S, Korpela R, Mervaala EM: Effects of high-calcium diets
with different whey proteins on weight loss and weight regain in high-
fat-fed C57BL/6 J mice. Br J Nutr 2009, 102:337–341.
14. Bowen J, Noakes M, Clifton PM: Appetite regulatory hormone responses
to various dietary proteins differ by body mass index status despite
similar reductions in ad libitum energy intake. J Clin Endocrinol Metab
15. Petersen BL, Ward LS, Bastian ED, Jenkins AL, Campbell J, Vuksan V: A whey
protein supplement decreases post-prandial glycemia. Nutr J 2009, 8:47.
16. Gunnarsson PT, Winzell MS, Deacon CF, Larsen MO, Jelic K, Carr RD, Ahren
B: Glucose-induced incretin hormone release and inactivation are
differently modulated by oral fat and protein in mice. Endocrinology 2006,
17. Takasaki K, Nakajima T, Ueno K, Nomoto Y, Higo K: Effects of combination
treatment with dipeptidyl peptidase IV inhibitor and sulfonylurea on
glucose levels in rats. J Pharmacol Sci 2004, 95:291–293.
18. Whey protein: Monograph. Altern Med Rev 2008, 13:341–347.
19. Haraguchi FK, Pedrosa ML, de Paula H, dos Santos RC, Silva ME:
Influência das proteínas do soro sobre enzimas hapáticas, perfil
Sousa et al. Lipids in Health and Disease 2012, 11:67 Page 7 of 9
lipídico e formação óssea de ratos hipercolesterolêmicos. Rev Nutr
20. Luhovyy BL, Akhavan T, Anderson GH: Whey proteins in the regulation of
food intake and satiety. J Am Coll Nutr 2007, 26:704S–712S.
21. Haraguchi FK, de Abreu WC, de Paula H: Proteínas do soro do leite:
composição, propriedades nutricionais, aplicações no esporte e
benefícios para a saúde humana. Rev Nutr 2006, 19:479–488.
22. Hulmi JJ, Lockwood CM, Stout JR: Effect of protein/essential amino acids
and resistance training on skeletal muscle hypertrophy: A case for whey
protein. Nutr Metab (Lond) 2010, 7:51.
23. Pal S, Ellis V, Ho S: Acute effects of whey protein isolate on cardiovascular
risk factors in overweight, post-menopausal women. Atherosclerosis 2010,
24. Barnett MP, Phillips AR, Harris PM, Cooper GJ: Impaired insulin secretion in
perfused pancreases isolated from offspring of female rats fed a low
protein whey-based diet. Jop 2008, 9:477–488.
25. Pacheco MTB, Dias NFG, Baldini VLS, Tanikawa C, Sgarbieri VCS: Propriedades
funcionais de hidrolisados obtidos a partir de concentrados protéicos de
soro de leite. Ciênc Tecnol Aliment 2005, 25:333–338.
26. Pal S, Ellis V: The acute effects of four protein meals on insulin, glucose,
appetite and energy intake in lean men. Br J Nutr 2010, 104:1241–1248.
27. Hackney KJ, Bruenger AJ, Lemmer JT: Timing protein intake increases
energy expenditure 24 h after resistance training. Med Sci Sports Exerc
28. Lan-Pidhainy X, Wolever TM: The hypoglycemic effect of fat and protein is
not attenuated by insulin resistance. Am J Clin Nutr 2010, 91:98–105.
29. Pilvi TK, Korpela R, Huttunen M, Vapaatalo H, Mervaala EM: High-calcium
diet with whey protein attenuates body-weight gain in high-fat-fed
C57Bl/6 J mice. Br J Nutr 2007, 98:900–907.
30. Muro Urista C, Alvarez Fernandez R, Riera Rodriguez F, Arana Cuenca A,
Tellez Jurado A: Review: Production and functionality of active peptides
from milk. Food Sci Technol Int 2011, 17:293–317.
31. Graf S, Egert S, Heer M: Effects of whey protein supplements on
metabolism: evidence from human intervention studies. Curr Opin Clin
Nutr Metab Care 2011, 14:569–580.
32. Gilbert JA, Bendsen NT, Tremblay A, Astrup A: Effect of proteins from
different sources on body composition. Nutr Metab Cardiovasc Dis 2011,
33. Dougkas A, Reynolds CK, Givens ID, Elwood PC, Minihane AM: Associations
between dairy consumption and body weight: a review of the evidence
and underlying mechanisms. Nutr Res Rev 2011, :1–24.
34. Madureira AR, Tavares T, Gomes AM, Pintado ME, Malcata FX: Invited
review: physiological properties of bioactive peptides obtained from
whey proteins. J Dairy Sci 2010, 93:437–455.
35. Baer DJ, Stote KS, Paul DR, Harris GK, Rumpler WV, Clevidence BA: Whey
protein but not soy protein supplementation alters body weight and
composition in free-living overweight and obese adults. J Nutr 2011,
36. Burton-Freeman BM: Glycomacropeptide (GMP) is not critical to whey-
induced satiety, but may have a unique role in energy intake regulation
through cholecystokinin (CCK). Physiol Behav 2008, 93:379–387.
37. Pichon L, Potier M, Tome D, Mikogami T, Laplaize B, Martin-Rouas C,
Fromentin G: High-protein diets containing different milk protein
fractions differently influence energy intake and adiposity in the rat. Br J
Nutr 2008, 99:739–748.
38. Pilvi TK, Storvik M, Louhelainen M, Merasto S, Korpela R, Mervaala EM: Effect
of dietary calcium and dairy proteins on the adipose tissue gene
expression profile in diet-induced obesity. J Nutrigenet Nutrigenomics
39. Pal S, Ellis V, Dhaliwal S: Effects of whey protein isolate on body
composition, lipids, insulin and glucose in overweight and obese
individuals. Br J Nutr 2010, 104:716–723.
40. Kasim-Karakas SE, Cunningham WM, Tsodikov A: Relation of nutrients and
hormones in polycystic ovary syndrome. Am J Clin Nutr 2007, 85:688–694.
41. Pal S, Ellis V: The chronic effects of whey proteins on blood pressure,
vascular function, and inflammatory markers in overweight individuals.
Obesity (Silver Spring) 2010, 18:1354–1359.
42. Pimentel GD, Mota JF, Oyama LM: Oxyntomodulin and obesity. Rev Nutr
43. Pimentel GD, Dornellas AP, Rosa JC, Lira FS, Cunha CA, Boldarine VT, de
Souza GI, Hirata AE, Nascimento CM, Oyama LM, et al:High-fat diets rich in
soy or fish oil distinctly alter hypothalamic insulin signaling in rats. J Nutr
Biochem 2012, 23:822–8.
44. Carvalheira JB, Ribeiro EB, Araujo EP, Guimaraes RB, Telles MM, Torsoni M,
Gontijo JA, Velloso LA, Saad MJ: Selective impairment of insulin
signalling in the hypothalamus of obese Zucker rats. Diabetologia 2003,
45. Ropelle ER, Flores MB, Cintra DE, Rocha GZ, Pauli JR, Morari J, de Souza CT,
Moraes JC, Prada PO, Guadagnini D, et al:IL-6 and IL-10 anti-inflammatory
activity links exercise to hypothalamic insulin and leptin sensitivity
through IKKbeta and ER stress inhibition. PLoS Biol 2010, 8.
46. Frid AH, Nilsson M, Holst JJ, Bjorck IM: Effect of whey on blood glucose
and insulin responses to composite breakfast and lunch meals in type 2
diabetic subjects. Am J Clin Nutr 2005, 82:69–75.
47. Li C, Chen P, Palladino A, Narayan S, Russell LK, Sayed S, Xiong G, Chen J,
Stokes D, Butt YM, et al:Mechanism of hyperinsulinism in short-chain 3-
hydroxyacyl-CoA dehydrogenase deficiency involves activation of
glutamate dehydrogenase. J Biol Chem 2010, 285:31806–31818.
48. Mortensen LS, Holmer-Jensen J, Hartvigsen ML, Jensen VK, Astrup A, de
Vrese M, Holst JJ, Thomsen C, Hermansen K: Effects of different fractions
of whey protein on postprandial lipid and hormone responses in type 2
diabetes. Eur J Clin Nutr 2012, In press.
49. Santoro S, Velhote MCP, Manzoni CE, Mechenas ASG, Strassmann V,
Scheinberg V: Adaptação digestiva: Uma nova proposta cirúrgica para
tratar a obesidade com base em fisiologia e evolução. Einstein 2003,
50. Mannucci E, Pala L, Ciani S, Bardini G, Pezzatini A, Sposato I, Cremasco F,
Ognibene A, Rotella CM: Hyperglycaemia increases dipeptidyl peptidase
IV activity in diabetes mellitus. Diabetologia 2005, 48:1168–1172.
51. Veldhorst MA, Nieuwenhuizen AG, Hochstenbach-Waelen A, van Vught AJ,
Westerterp KR, Engelen MP, Brummer RJ, Deutz NE, Westerterp-Plantenga
MS: Dose-dependent satiating effect of whey relative to casein or soy.
Physiol Behav 2009, 96:675–682.
52. Pinto LC, Ricardo ED, Leitao CB, Kramer CK, Zanatta CM, Gross JL, Canani LH:
Inadequate blood pressure control in patients with type 2 diabetes
mellitus. Arq Bras Cardiol 2010, 94:651–655.
53. Takahashi MM, de Oliveira EP, de Carvalho AL, de Souza Dantas LA, Burini
FH, Portero-McLellan KC, Burini RC: Metabolic syndrome and dietary
components are associated with coronary artery disease risk score in
free-living adults: a cross-sectional study. Diabetol Metab Syndr 2011, 3:7.
54. Lee YM, Skurk T, Hennig M, Hauner H: Effect of a milk drink supplemented
with whey peptides on blood pressure in patients with mild
hypertension. Eur J Nutr 2007, 46:21–27.
55. Tome D, Schwarz J, Darcel N, Fromentin G: Protein, amino acids, vagus
nerve signaling, and the brain. Am J Clin Nutr 2009, 90:838S–843S.
56. Valentino MA, Lin JE, Snook AE, Li P, Kim GW, Marszalowicz G, Magee MS,
Hyslop T, Schulz S, Waldman SA: A uroguanylin-GUCY2C endocrine axis
regulates feeding in mice. J Clin Invest 2011, 121:3578–3588.
57. Pimentel GD, Zemdegs JC: Foods and nutrients modulates the release of
anorexigenic gastrointestinal hormones. Acta Med Port 2010, 23:891–900.
58. Pimentel GD, Micheletti TO, Pace F, Rosa JC, Santos RV, Lira FS: Gut-central
nervous system axis is a target for nutritional therapies. Nutr J 2012, 11:22.
59. Foltz M, Ansems P, Schwarz J, Tasker MC, Lourbakos A, Gerhardt CC:
Protein hydrolysates induce CCK release from enteroendocrine cells
and act as partial agonists of the CCK1 receptor. J Agric Food Chem
60. Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ:
Hypothalamic mTOR signaling regulates food intake. Science 2006,
61. Ropelle ER, Pauli JR, Fernandes MF, Rocco SA, Marin RM, Morari J, Souza KK,
Dias MM, Gomes-Marcondes MC, Gontijo JA, et al:A central role for
neuronal AMP-activated protein kinase (AMPK) and mammalian target
of rapamycin (mTOR) in high-protein diet-induced weight loss. Diabetes
62. Kume H, Okazaki K, Sasaki H: Hepatoprotective effects of whey protein on
D-galactosamine-induced hepatitis and liver fibrosis in rats. Biosci
Biotechnol Biochem 2006, 70:1281–1285.
63. Heilbronn LK, de Jonge L, Frisard MI, DeLany JP, Larson-Meyer DE, Rood J,
Nguyen T, Martin CK, Volaufova J, Most MM, et al:Effect of 6-month calorie
restriction on biomarkers of longevity, metabolic adaptation, and
oxidative stress in overweight individuals: a randomized controlled trial.
JAMA 2006, 295:1539–1548.
Sousa et al. Lipids in Health and Disease 2012, 11:67 Page 8 of 9
64. Cruz-Guilloty F, Perez VL: Molecular medicine: Defence against oxidative
damage. Nature 2011, 478:42–43.
65. Van Gaal LF, Mertens IL, De Block CE: Mechanisms linking obesity with
cardiovascular disease. Nature 2006, 444:875–880.
66. Mercer JR, Yu E, Figg N, Cheng KK, Prime TA, Griffin JL, Masoodi M, Vidal-
Puig A, Murphy MP, Bennett MR: The mitochondria-targeted antioxidant
MitoQ decreases features of the metabolic syndrome in ATM+/−/ApoE
−/−mice. Free Radic Biol Med 2012, 52:841–849.
67. Ebaid H, Salem A, Sayed A, Metwalli A: Whey protein enhances normal
inflammatory responses during cutaneous wound healing in diabetic
rats. Lipids Health Dis 2011, 10:235.
68. Hamad EM, Taha SH, Abou Dawood AG, Sitohy MZ, Abdel-Hamid M:
Protective effect of whey proteins against nonalcoholic fatty liver in rats.
Lipids Health Dis 2011, 10:57.
69. Zavorsky GS, Kubow S, Grey V, Riverin V, Lands LC: An open-label dose–
response study of lymphocyte glutathione levels in healthy men and
women receiving pressurized whey protein isolate supplements. Int J
Food Sci Nutr 2007, 58:429–436.
70. Chitapanarux T, Tienboon P, Pojchamarnwiputh S, Leelarungrayub D: Open-
labeled pilot study of cysteine-rich whey protein isolate
supplementation for nonalcoholic steatohepatitis patients. J Gastroenterol
Hepatol 2009, 24:1045–1050.
71. de Aguilar-Nascimento JE, Prado Silveira BR, Dock-Nascimento DB: Early
enteral nutrition with whey protein or casein in elderly patients with
acute ischemic stroke: a double-blind randomized trial. Nutrition 2011,
72. Xu R, Liu N, Xu X, Kong B: Antioxidative effects of whey protein on
peroxide-induced cytotoxicity. J Dairy Sci 2011, 94:3739–3746.
73. Takayanagi T, Sasaki H, Kawashima A, Mizuochi Y, Hirate H, Sugiura T, Azami
T, Asai K, Sobue K: A new enteral diet, MHN-02, which contains abundant
antioxidants and whey peptide, protects against carbon tetrachloride-
induced hepatitis. JPEN J Parenter Enteral Nutr 2011, 35:516–522.
74. Abdel-Aziem SH, Hassan AM, Abdel-Wahhab MA: Dietary supplementation
with whey protein and ginseng extract counteracts oxidative stress and
DNA damage in rats fed an aflatoxin-contaminated diet. Mutat Res 2011,
75. Gad AS, Khadrawy YA, El-Nekeety AA, Mohamed SR, Hassan NS, Abdel-
Wahhab MA: Antioxidant activity and hepatoprotective effects of whey
protein and Spirulina in rats. Nutrition 2011, 27:582–589.
76. Yalcin AS: Emerging therapeutic potential of whey proteins and
peptides. Curr Pharm Des 2006, 12:1637–1643.
Cite this article as: Sousa et al.:Dietary whey protein lessens several risk
factors for metabolic diseases: a review. Lipids in Health and Disease 2012
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