2. Scientific Program, ISCSEM, May 26, 2012
• The nutrient-sensitive kinase mTORC1
• Milk: an endocrine mTORC1-activating signalling
system of mammalian evolution
• Milk consumption and insulin resistance
• Milk consumption and type 2 diabetes
• Milk consumption and obesity
• Milk consumption and cancer
• Milk consumption and acne
• Conclusion
4. mTORC1: mammalian target of rapamycin complex 1
300 kD multiprotein complex
P
S6K1 S6K1
N-terminal C-terminal
PI3K-like kinase
5. mTORC1: a central metabolic regulator
of all mammalian cells
mTORC1
Protein Lipid Cell Cell Auto-
synthesis synthesis growth proliferation phagy
6. Nutrient
signalling
is
integrated
at
mTORC1
Leucine Insulin IGF-1 Glucose
LAT IR IGF1R GLUT
IRS-‐1
PI3K PTEN ATP
Leucine Akt
TSC1/TSC2
AMPK
Rag GTPases Rheb
Insulin
resistance
inactive
mTORC1
mTORC1 activated
Translocation
4EBP1 SREBP S6K1
7. Reduced TOR signalling in C. elegans by impaired
amino acid- (pep-2 deletion) and daf-2 signalling (daf-2
deletion) strongly extends life span
C. elegans
Meissner B et al. (2004)
9. Functional and structural role of L-leucine
L-leucine: a branched-chain essential amino acid
• Most important amino acid for activation of mTORC1
• Important component of the leucine zipper (myc, fos, jun)
• Structural precursor for de novo-lipid synthesis
• Structural component of protein synthesis (muscle protein)
• Precursor of acetoacetyl-CoA (citrate cycle) gluconeogenesis
• Leucine: the „hidden messenger“ of milk´s signalling proteins
10. Milk: a mammary gland secretion that functions
as a donor of easily accessible leucine
Milk
an endocrine mTORC1-activating signalling
system of mammalian evolution
11. Leucine and BCAA content of foods
Protein source Leucine BCAAs
Whey protein isolate 14% 26%
Milk protein 10% 21%
Egg protein 8.5% 20%
Muscle protein 8.0% 18%
Soy protein isolate 8.0% 18%
Wheat protein 7.0% 15%
Millward DJ et al. (2008)
12. Comparison of the insulinotropic effects
of various protein test meals
each contained 18.2 g protein
12 healthy volunteers
Nilsson M et al. (2004)
13. Amino acid content of different test meals
(mg/serving)
Nilsson M et al. (2004)
19. Strong insulinotropic effects of whey protein
and BCAAs, especially of leucine
Whey protein
Glucose
Nilsson M et al. (2007)
20. Highest postprandial insulin levels after a milk protein
meal compared with soy protein and fish (cod) protein
Milk = Cottage cheese (80% casein + 20% whey)
von Post-Skagegard M et al. (2006)
21.
Signalling proteins versus structural proteins
Western diet Paleolithic diet
Signalling proteins Structural proteins
promoting growth & proliferation providing muscle function
Whey proteins
Meat / fish proteins
Highest content of leucine (14%) High leucine content (8%)
small soluble proteins with low MW complex proteins with high MW
fast intestinal hydrolysis retarded intestinal hydrolysis
High postprandial leucine pulses Slow postprandial rise in leucine
High insulin secretion Moderate insulin secretion
High insulinemic index > 100 Low insulinemic index ≈ 50
22. Functional differences in leucine-TORC1-signalling
of various common protein sources
Dietary proteins
Animal proteins Plant proteins
natural plant-derived
mTORC1 inhibitors
Dairy
proteins
Meat proteins Fish proteins
Caseins Whey proteins
Leucine
Adipogenesis
mTORC1 β-Cell proliferation
Insulin S6K1
IRS-1
Obesity Insulin resistance β-Cell apoptosis
T2D
23. Milk: an mTORC1-driving signalling system
Whey proteins Caseins
Fast intestinal hydrolysis Slow intestinal hydrolysis
Leucine mTORC1 Amino acids
β
β-Cell
Insulin
Leu Insulin IGF-1
IRS1
Peripheral cell
Leu mTORC1
4EBP1
S6K1
Cell growth
Cell proliferation
28. Amino acid-mTORC1-S6K1-mediated insulin resistance
via inhibitory phosphorylation of IRS-1
(insulin receptor substrate-1)
Leucine
Boura-Halfon S et al. (2009)
30. Overactivation of S6K1 as a cause of human insulin
resistance during increased amino acid availability
Tremblay F et al. (2005)
31. mTORC1 via S6K1 increases insulin resistance
in humans (11 healthy men)
Krebs M et al. (2007)
32. mTORC1 via S6K1 increases insulin resistance
in humans (11 healthy men)
Krebs M et al. (2007)
33. Amino acid over-nutrition in humans induced
S6K1-mediated inhibitory phosphorylation of
IRS-1 Ser-1101 as a cause of insulin resistance
Tremblay F et al. (2007)
34. Amino acids + insulin induced S6K1-mediated
inhibitory phosphorylation of IRS-1 Ser-1101
within 30 minutes
Tremblay F et al. (2007)
35. A more critical view on „insulin resistance“ is
urgently needed, which has primarily to
appreciate tissue-specific alterations of insulin
signalling and not fasting parameters obtained
from venous blood outside the organ system
• Insulin resistance is not a medical „blood parameter“
• but a tissue-specific state and degree of IRS-1-dependent
downstream insulin signalling
• HOMA measurements rely only on fasting levels of insulin and glucose
• and do not reflect the real state of insulin resistance of any specific
insulin-dependent tissue like muscle, liver or adipose tissue
36. Most nutritional studies do not consider the
biochemical kinetics of fast signalling hormones
and nutrients in cell metabolism
• The mTORC1 system responds within minutes to
changes of amino acid- or growth hormone levels.
• The cell has to respond quickly to changes of nutrient
availability and withdrawal to maintain cell homeostasis.
• Insulin exhibits fast kinetic (minutes) postprandial
responses to changes of glucose and amino acids.
• Overnight fasting serum levels of insulin, glucose or amino
acids do not reflect the daily metabolic burden but show
metabolic events at their minimum.
37. Milk protein versus meat consumption in 8 y-old boys
increased fasting insulin, insulin resistance and
β-cell function (7 days intervention)
Milk-group (53 g milk protein) Meat group (53 g meat protein)
?
Hoppe C et al. (2005)
Weakness: Only fasting levels and no postprandial effects have been measured in this
study. Insulin resistance has been determined by HOMA and calculated from fasting levels
38. 10 days-intervention in 11 adults consuming
either 2.5 l semi-skimmed milk or cola
?
Hoppe C et al. (2009)
Measurement of fasting serum values and not postprandial parameters. HOMA
data have been calculated from fasting serum levels of glucose and insulin and not
from functional postprandial tests like OGTT or a clamp test.
39. Study of whey protein versus casein on insulin fasting
levels and HOMA2 in overweight/obese individuals
(12 weeks)
G: Glucose control group 27 g glucose (n=25)
W: Whey group (27 g whey protein concentrate) (n=25)
C: Casein group (27 g sodium caseinate) (n=20) Pal S et al. (2010)
G G C
?
C
W W
Critical remark: This study measured HOMA data refect fasting insulin
fasting insulin levels and not levels when fasting glucose has not
postprandial insulin responses changed
40. Of biological importance is not the insulin fasting level
but the postprandial insulin secretion, which reflects
the metabolic burden (AUC) of the secreting β-cell
?
Overnight
AUC fas4ng
level
Milk = Cottage cheese (80% casein + 20% whey)
von Post-Skagegard M et al. (2006)
41. Conclusions:
Milk consumption and insulin resistance
• Available experimental data (Hoppe et al.; Pal et al.) do not reflect
biochemical reality of milk-induced insulin resistance as they are
only based on fasting serum levels of insulin, glucose and HOMA.
• Experimental studies in humans with infused amino acids
resembling real postprandial amino acid challenge provided
evidence for increased inhibitory IRS1-phosphorylation.
• Determination of tissue mTORC1 activity by measuring 4EBP1-,
S6K1- and IRS1-phosphorylation after a milk protein challenge
versus meat-, fish- or soy protein are urgently needed to
characterize milk/leucine-mediated insulin resistance of other non-
dairy protein sources.
42. Does persistent milk consumption
disturb β-cell homeostasis?
Milk consumption and type 2 diabetes
43. Dietary protein intake and risk of T2D
• Hong Kong Dietary Survey
more vegetables, fruits and fish
14% lower risk of T2D
more meat and milk products
39% greater risk of T2D (Hu R et al. 2011)
• Meta-analysis of the Health Professionals Follow Up Study,
Nurses Health Study I and Nurses Health Study II
red meat consumption
increased risk of T2D (Pan A et al. 2011)
44. T2D is an mTORC1-driven disease
• Zoncu R et al. (2011)
mTOR: from growth signal integration to cancer, diabetes and ageing.
Nature Rev 12: 21
• Proud CG (2010)
mTOR signalling in health and disease.
Biochem Soc Trans 39: 431
• Mieulet V et al. (2010)
Tuberous sclerosis complex: liking cancer to metabolism.
Trends Mol Med 16: 329
• Dann SG et al. (2007)
mTOR Complex 1-S6K1 signaling: at the crossroads of obesity, diabetes
and cancer.
Trends Mol Med 13: 252
45.
BCAAs
and
leucine
in
β-‐cell
mTORC1
ac@va@on
• Xu
G
et
a.
(1998)
Branched-‐chain
amino
acids
are
essen@al
in
the
regula@on
of
PHAS-‐I
and
p70
S6
kinase
by
pancrea@c
β-‐cells.
• Xu
G
et
al.
(2001)
Metabolic
regula@on
by
leucine
of
transla@on
ini@a@on
through
the
mTOR-‐signaling
pathway
by
pancrea@c
β-‐cells.
• McDaniel
ML
et
al.
(2002)
Metabolic
and
autocrine
regula@on
of
the
mammalian
target
of
rapamycin
by
pancrea@c
β-‐cells.
• Kwon
G
et
al.
(2004)
Signaling
elements
involved
in
the
metabolic
regula@on
of
mTOR
by
nutrients,
incre@ns,
and
growth
factors
in
islets.
47. Effects of high dietary leucine intake on β-cell mTORC1
signalling during periods of growth and adulthood
High milk High milk
intake in intake
pregnancy in puberty
Leu Leu Leu
Leu
Fetal life Post- Puberty Adulthood
natal
?
High Leu of Milk and milk
Infant formula products
Diabetogenic effects by impaired Early onset of T2D by persistent
β-cell development and disturbed mTORC1-mediated β-cell proliferation
postnatal metabolic programming and early β-cell apoptosis
48. Neurogenin3 expression: the critical step for the
development of endocrine cells in the pancreas
Jorgensen MC et al. (2007)
49. Crititical role of high leucine intake during pregnancy for
fetal β-cell differentiation and β-cell mass in the rat
Leucine
mTORC1
HIF1α
PDX-‐1
expressing
NGN3-‐expressing
islet
progenitors
islet
progenitors
β-cell formation
Increased risk
of T2D
Rachdi L et al. (2012)
50. Increased leucine intake during pregnancy
increases birthweight
Rat
Human
neonate
Rachdi L et al. (2012) Olsen
SF
et
al.
(2007)
51. Breast feeding in comparison to formula feeding
protects against the development of T2D
Owen CG et al. (2006)
52. Cow milk-based infant formula-feeding exceeds
leucine-, IGF-1- and C-peptide serum concentrations
in comparison to breast-feeding
Socha P et al.(2011) Melnik BC et al. (2012)
53. Persistent milk intake may disturb β-cell homeostasis
by continued stimulation of β-cell proliferation
57. Intitial increase and later decrease of β-cell numbers in
mTORC1-hyperactivated β-cells
Shigeyama Y et al. (2008)
58. High fat-high casein diet promoted excessive β-cell loss
by apoptosis in prediabetic nonobese diabetic mice
A high fat-high protein diet
(43%fat, 38% casein,19% carbohydrates)
has promoted a higher reduction of β-cell mass
(84%) and more apoptotic β-cells at 30 weeks
than
a high fat-low protein diet
(39% fat, 17% casein, 43% carbohydrates),
which was associated with a lower reduction
of β-cell mass (14%) weeks
Linn T et al. (1999)
59. Misleading results of epidemiological studies analysing
the risk of „dairy consumption“ for T2D
• Questionaires of most studies have selected insufficient and incomparable data
like: Total dairy consumption; Dairy intake; Milk and dairy food
Low fat dairy products versus high fat dairy products
Milk/milk products except cheese and cheese
• Meta-analyses performed on the basis of these data are not appropriate.
• All studies are performed in milk consuming populations and are not controlled
against a non-milk-drinking population.
• No intervention study with and without milk protein intake over diabetes-
relevant long time periods of several decades has been performed.
• No study has calculated total daily intake of milk protein mass in gram
• No study has considered the insulinotropic functionality of milk proteins and
has differentiated between highly insulinotropic whey protein intake and less
insulinotropic casein protein intake
• No study has evaluated total daily leucine intake of dairy proteins against the
background of other animal and plant-protein-derived leucine intake.
• Most studies have been performed in adults and no study has considered early
sensitive perinatal periods of metabolic programming.
60. Conclusions
(I)
Milk
and
type
2
diabetes
• Milk is an endocrine signalling system of mammalian evolution.
• Milk proteins via leucine activate β-cell mTORC1.
• mTORC1 plays a pivotal role in the regulation of insulin synthesis,
insulin secretion as well as β-cell mass homeostasis linking milk
protein consumption to the pathogenesis of T2D.
• Milk proteins are highly insulinotropic signalling proteins in
comparison to structural proteins like meat and fish.
• Increased leucine intake during pregnancy may impair fetal β-cell
mass differentiation via mTORC1-HIF1α-mediated suppression of
NGN3-progenitor cells, thus reducing β-cell mass.
61. Conclusions
(II)
• Infant formula feeding provides higher amounts of leucine than
breast-feeding, a possible explanation for the lower prevalence rates
of T2D in breast-fed individuals.
• Exaggerated leucine-driven mTORC1 signalling by persistent milk
consumption and high meat intake may accelerate the onset of
T2D by induction of replicative β-cell senescence and apoptosis.
• The transition of China from a leucine-poor vegetable-based to a
leucine-rich Western diet explains the increase of mTORC1-driven
diseases like T2D as shown in the Hong Kong Dietary Survey.
Melnik BC (2012) Leucine signaling in the pathogenesis of type 2 diabetes and obesity.
World J Diabetes, 3: 38-53
Melnik BC (2012) Excessive leucine-mTORC1-signalling of cow milk-based infant formula:
the missing link to understand early childhood obesity. J Obesity, 2012: article ID 197653
62. Conclusion
(III)
• The
glucose
lowering
effects
of
milk
protein
consump4on
should
not
be
mistaken
as
a
protec4ve
mechanism
in
the
pathogenesis
of
T2D
• Most
epidemiological
studies
which
have
addressed
the
dairy-‐T2D
rela4onship
are
misleading
as
they
did
not
precisely
differen4ate
between
intake
of
highly
insulinotropic
whey
protein-‐based
milk/products
and
less
insulinotropic
casein-‐based
milk
products.
• Study
determinants
like
„dairy
product
consump4on
„total
dairy
intake“,
„high
fat
versus
low
fat
dairy
products“
and
short
study
periods
(<
12
yrs)
of
adult
subjects
are
not
suitable
to
detect
the
rela4onship
between
persitent
milk
consump4on
and
T2D
63. Conclusions (IV)
• Future studies have to differentiate between
– high insulinotropic whey-based milk products and
– less insuinotropic casein-based milk products and
– should calculate total daily leucine intake against the background
of meat/fish-derived leucine intake
– and should consider the effect of cow milk consumption over the
whole life span with special attention to intrauterine and perinatal
phases of growth and metabolic programming.
64. Is milk an anabolic system that promotes
adipogenesis and obesity?
Milk consumption and obesity
65. The adipogenic effects of milk
• Leucine stimulates mTORC1 and S6K1- and 4EPB1 phosphorylation of
adipocytes.
• The mTORC1 inhibitor rapamycin inhibits adipocyte differentiation.
• mTORC1 stimulates lipid synthesis by phosphorylation of lipin1, the
stimulator of nuclear SREBP-1 activation
• mTORC1 activates PPARγ, the key transcription factor of adipogenesis.
• Milk increases postprandial insulin serum levels. Insulin inhibits lipolysis
and stimulates cellular lipid accumulation.
• Milk consumption increases serum levels of IGF-1, which promotes the
differentiation of pre-adipocytes to adipocytes.
• mTORC1 plays a fundamental role in the differentiation of
mesenchymal stem cells into adipocytes.
• Milk consumption in children increased BMI.
• Breast feeding in comparison to infant formula feeding has a preventive
effect on the development of obesity.
66. Amino acid effects on translational repressor
4E-BP1 are mediated primarily by L-leucine in
isolated adipocytes
Fox HL et al. (1998)
67. Amino acids stimulate phosphorylation of S6K1
and organization of rat adipocytes
into multicellular clusters
Leu
16x
Fox HL et al. (1998)
69. Amino acids via mTORC1 increase lipin phosphorylation
in a rapamycin-sensitive manner linking the nutrient-
sensing (mTORC1) pathway to adipocyte development
Huffman TA et al. (2002)
70. mTORC1 controls nuclear SREBP
by phosphorylation of lipin1
Peterson
TR
et
al.
(2011)
Peterson TR et al. (2011)
76. mTORC1 substrate S6K1 promotes differentiation of
adipocytes from multipotent stem cells
S6K1-/-
mice
NCD=
normal chow diet
HFD=
high fat diet
Carnevalli LS et al. (2010)
77. mTORC1 suppresses lipolysis, stimulates
lipogenesis, and promotes fat storage
Activation of mTORC1 in 3T3-L1 adipocytes
• inhibits expression of adipose triglyceride lipase (ATGL)
• and inhibits expression of hormone-sensitive lipase (HSL) at the
level of transcription
• suppresses lipolysis
• increases de novo lipogenesis
• promotes intracellular accumulation of triglycerides
Chakrabarti P et al. (2010)
78. Conclusions: Milk and adipogenesis
• Milk consumption activates adipogenesis by up-
regulation of mTORC1-SREBP- and mTORC1-PPARγ-
signalling.
• Cow´s milk based infant formula feeding increases
serum levels of the mTORC1 activators leucine, insulin
and IGF-1 and thus increases the risk of early mTORC1-
driven adipogenic programming.
• In mice mTORC1-S6K1 hyperactivity increased the
differentiation of adipocytes from mesenchymal
stem cells and increased the number of adipocytes
during life time with the risk of adipose tissue
hyperplasia and hypertrophy.
79. Does milk consumption increase the risk
of common Western cancers?
Milk consumption and cancer
84. Does milk consumption increase the risk
of the most common cancer in men?
Milk consumption and prostate cancer
85. Incidence rate of prostate cancer and
per capita milk consumption
Ganmaa D et al. (2002)
86. Strong epidemiological evidence for the
association between dairy protein intake and
prostate cancer
Prospective
study
over 8.7 years
European multi-
centric study
142,251 men
35 g increase in
dairy protein
associated with
a risk increase
of prostate
cancer of 32%
Allen NE et al. (2008)
88. Increased risk of advanced prostate cancer in men with
daily milk consumption during adolescence
(Island Study)
Daily milk consumption during adolescence
has been associated with
a 3.2-fold increased risk of advanced prostate cancer
Torfadottir JE et al. (2011)
89. Milk consumption promotes the progression
of prostate cancer
Men with the highest versus lowest intake of whole milk were at
an increased risk of prostate cancer progression
Pettersson A et al. (2012)
90. Milk stimulates growth of prostate cancer cells
in vitro
Cow´s milk stimulated the growth of LNCaP prostate cancer cells
in each of 14 experiments
producing an average increase in growth rate of 30%.
Tate PL et al. (2011)
91. Common mutations or aberrations in the mTORC1
signalling cascade of prostate cancer cells
Insulin&&& %IGF$1&
&&IR% %IGF1R%
PI3K% IRS$1& RAS&
PTEN% RAF&
PDK1&
Akt% MEK&
%%%%%Androgen& mTORC2%
&FoxO1& ERK1/2&
PRAS40&
&&TSC1&/&TSC2% AMPK&&&&&&&&&&&LKB1&&
Leucine& &LAT% &Leucine%
ATP&
Rag%GTPases% Rheb%
&&&&&&&&&Glu& GLUT% Glucose&
mTORC1& mTORC1!%%%!
!lysosomal!
inac&ve!!
Estrogens&
4EBP1& S6K1&
Increased&transcripIon,&mRNA&translaIon,&ribosome&biogenesis,&&
cellular&growth,&proliferaIon,&and&cell&survival&&
Prostate%tumorigenesis% Fig.&3&
Melnik BC et al. (2012)
93. Conclusions:
Milk consumption and prostate cancer
• Most epidemiological studies support the association between milk
protein consumption and increased risk of prostate cancer.
• In vitro evidence confirms the stimulatory effect of milk on the growth
of prostate cancer cells.
• Growth-promoting mTORC1-mediated milk signalling stimulates
already activated cellular pathways of mutated prostate cancer cells,
which results in hyper-activated mTORC1 signalling, thus promoting
the development and progression of prostate cancer.
• Milk consumption during prostate morphogenesis and sexual
mTORC1-dependent maturation and differentiation of the prostate
during puberty may stimulate tumorigenesis and may increase the
risk of advanced prostate cancer in adulthood.
94. Does milk consumption increase the risk
of the most common cancer in women?
Milk consumption and breast cancer
95. Milk consumption: a suspected dietary risk
factor of breast cancer and ovarian cancer
96. Relative increase in the consumption of milk
and dairy proteins in Japan after World War II
Milk and dairy products
Li XM et al. (2003)
98. Correlation between per capita milk consumption
and incidence rates of breast cancer
Ganmaa D et al. (2005)
99. High mammographic breast density is a risk
factor of breast cancer which correlates with
increased serum levels of IGF-1
100. Milk promotes the progression of DMBA-induced
mammary tumors in rats
101. Experimental design of the study of DMBA-induced
mammary tumors in rats to dietary cow´s milk exposure
5 mg anthracen
DMBA
Carcinogen
Rats with
breast cancer
Rat chow without milk Rat chow with
proteins commercial milk
?
Tumor incidence, tumor numbers and tumor volume
102. Milk intake increased incidence, tumor numbers and
tumor volume of DMBA-induced mammary tumors in rats
Milk (whole + nonfat)
Tumor incidence Control
Milk (whole + nonfat)
Tumor numbers Control
Milk (whole + nonfat)
Tumor volume
Control
Qin LQ et al. 2007
103. Dose-dependent increase in breast cancer
risk by daily milk consumption
• Study of 25 892 Norwegian women
(Cancer register of Norway)
• Daily intake of > 750 ml whole milk
increased the relative breast cancer risk by 2.91
• in comparison to women with < 150 ml milk intake, who
exhibited a relative risk of 1.0
Gaard M et al. (1995)
104. Commercial milk produced from pregnant cows
contains substantial amounts of pregnancy-
derived estrogens, well-known breast cancer-
promoting hormonal stimuli
105. The association between birthweight
and breast cancer
• Milk consumption during pregnancy increases birthweight
Milk protein Increased Increased
intake during birthweight risk of breast
pregnancy cancer
107. Conclusions (I):
Milk consumption and breast cancer (BC)
• Worldwide milk and dairy protein per capita intake correlates with the
incidence rate of BC.
• Epidemiological evidence supports the association between milk protein
consumption and increased serum levels of IGF-1.
• Increased serum IGF-1 levels are associated with increased risk of BC.
• Increased serum levels of IGF-1 are associated with increased
mammographic breast density, a high risk factor of BC.
• Growth-promoting mTORC1-mediated milk signalling stimulates cellular
pathways of mutated BC cells, which results in hyper-activated
mTORC1 signalling, thus promoting the progression of BC.
108. Conclusions (II):
Milk consumption and breast cancer (BC)
• Milk consumption of DMBA-induced mammary tumors in rats increased
tumor incidence, tumor numbers and tumor volume.
• Estrogens introduced into the human food chain by milk and milk
product consumption of pregnant cows may be an important co-
stimulatory factor increasing BC-promoting mTORC1 signalling
• There appears to be a dose-dependent increase of BC risk by
increased daily milk intake of women in Norway.
• Milk protein intake during pregnancy may not only increase infant´s
birthweight but may deviate developmental mTORC1-dependent
pathways of mammary gland morphogenesis increasing the risk of BC
later in life.
110.
Pathogenesis of acne
Follicular hyperproliferation
Hyperproliferation and Follicular and peri-
hyperplasia of sebaceous comedo follicular inflammation
glands formation
111. Common types of acne
Acne comedonica Moderate acne Severe acne
with sehorrhea papulopustulosa papulopustulosa
112. Acne: a disease of Western civilization
Cordain L et al. (2002)
113. Systematic meta-analysis of studies related to
the association between diet and acne
Spencer EH et al. (2009)
114. Improvement of acne by glycemic load reduction
At baseline After 12 weeks
Smith RN et al. 2007
115. Acne improvement by reduction of glycemic load
Before diet During diet
Kwon HH et al. (2012)
SREBP expression
116. Nurse Health Study (II) USA
retrospective cohort study (n = 47 355)
Adebamowo CA et al. (2005)
117. Growing Up Today Study USA
(prospective cohort study)
• 4273 boys
and
• 6094 girls
age range 9-15 years
Significant correlation between daily milk intake,
especially skim milk, and acne prevalence
Adebamowo CA et al. (2006, 2008)
118. Clinical evidence for the acne-promoting effect
of milk, especially skim milk
Di Landro A et al. (2012)
119. Paleolithic versus Western diet
Science
326,
Dezember
2009
Evolu7on
of
Diseases
of
Modern
Environments
Charité
University
Medicine
Berlin,
Humbold
University,
120. Whey protein abuse
in the body building environment
Whey acne
80
g
Whey
protein
=
12
L
milk
Leucine + BCAAs
Insulin + IGF-1
DHEAS
mTORC1
122. Increased prevalence of prostate cancer in
patients with severe long-lasting acne
The cause for this relationship should not be explained by the
appearance of P. acnes in the prostate gland
but most likely by the overlap of exaggerated mTORC1 signalling
in sebaceous glands promoting acne and exaggerated mTORC1
signal transduction promoting aberrant prostate differentiation
during sexual maturation
Sutcliffe S et al. (2007)
124. Conclusions:
Milk consumption and acne
• Epidemiological evidence strongly supports the association
bewtween milk consumption and acne.
• Recent clinical evidence confirmed the association between milk
consumption, especially skim milk consimption and acne.
• Milk signalling by increasing insulin and IGF-1 serum levels mimics
the endocrine signalling of puberty.
• High glycemic load of Western diet combined with milk intake in a
synergistical fashion augment mTORC1 signalling of the sebaceous
follicle increasing sebaceous lipid synthesis (seborrhea) and
promoting keratinocyte proliferation (comedo formation).
• Dietary intervention in acne is of crucial importance. Paleolithic type
diets provide a great chance for the prevention of acne, a visible
mTORC1-driven skin disease of Western malnutrition.
125. Anthropological conclusions
• The dietary change from less insulinotropic and less mTORC1-
activating structural proteins like meat and fish to increased
consumption of signalling proteins for mammalian neonatal growth
promotes exaggerated mTORC1-signalling – the crucial underlying
cause of all chronic mTORC1-driven diseases of civilization like
fetal macrosomia, acne, obesity, type 2 diabetes, cancer and most
likely neurodegenerative diseases.
• Permanent milk consumption by continued and increasing exposure
to the endocrine growth-promoting species-specific signalling system
of Bos taurus is a violation against human´s natural endocrine
homeostasis and against the laws of human´s natural physiology.
126. Comparison between populations with
high versus moderate dietary mTORC1 activity
High flux of milk-derived Consumption of less insulinotropic
insulinotropic amino acids amino acids derived from fish or meat
combined with high load of combined with
hyperglycemic carbohydrates low glycemic carbohydrates
Western diet Paleolithic diet
127. Milk-driven mTORC1 signalling and
mTORC1-associated diseases of civilization
Fetal macrosomia with
increased birthweight
Obesity
mTORC1 Type 2 diabetes
Insulin resistance
Cancer: prostate, breast
Acne
128. It´s never too late for a change:
We are Homo sapiens and not Homo bovinus
Thank you for your attention !
129. References
Literature request: Melnik@t-online.de
• Melnik B (2009) Milk consumption: aggravating factor of acne and promotor of
chronic diseases of Western societies. J Dtsch Dermatol Ges 7: 364-70.
• Melnik BC (2009) Milk – the promoter of chronic Western diseases. Med
Hypotheses 77: 631-9.
• Melnik BC (2011) Milk signalling in the pathogenesis of type 2 diabetes. Med
Hyptheses 76: 553-9.
• Melnik BC (2011) Evidence for acne-promoting effects of milk and other
insulinotropic dairy products. Clemens RA, Hernell O, Michaelsen KF (eds): Milk and
Milk Products in Human Nutrition. Nesté Nutr Inst Workshop Ser Pediatr Program, vol.
67, pp 131-145.
• Melnik BC (2012) Excessive leucine-mTORC1-signalling of cow milk-based infant
formula: the missing link to understand early childhood obesity. J Obesity 2012:
1-14, article ID 197653
• Melnik BC (2012) Leucine signaling in the pathogenesis of type 2 diabetes and
obesity. Word J Diabetes 3: 38-53.
• Melnik BC (2012) Dietary intervention in acne. Attenuation of increased mTORC1
signaling promoted by Western diet. Dermatoendocrinology 4:1: 1-13
• Melnik BC (2012) Diet in acne: further evidence for the role of nutrient signalling
in acne pathogenesis. Acta Derm Venereol 92: 228-31.
