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Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
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Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
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Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
Milk signaling_Dr. Melnik, NutriScience, Portugal, 2012
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  • 1. Milk Signalling andWestern Diseases Bodo C. Melnik University of Osnabrück Germany
  • 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
  • 3. IntroductionThe nutrient-sensitive kinase mTORC1
  • 4. mTORC1: mammalian target of rapamycin complex 1                           300 kD multiprotein complex P S6K1 S6K1N-terminal C-terminal PI3K-like kinase
  • 5. mTORC1: a central metabolic regulator of all mammalian cells mTORC1Protein 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 impairedamino acid- (pep-2 deletion) and daf-2 signalling (daf-2 deletion) strongly extends life span C. elegans Meissner B et al. (2004)
  • 8. mTORC1: the central hub of metabolism Zoncu R et al. (2011)
  • 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 foodsProtein source Leucine BCAAsWhey 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)
  • 14. Postprandial leucine increase Nilsson M et al. (2004)
  • 15. Whey proteins induce the stongest effects on postprandial insulin serum levels Nilsson M et al. (2004)
  • 16. Whey proteins: the predominating insulin secretagogues of animal proteins Nilsson M et al. (2004)
  • 17. Leucine exhibits the highest insulinogenic index Nilsson M et al. (2004)
  • 18. Whey proteins: the strongest inducers of GIP 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 proteinmeal 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          LeucineAdipogenesis mTORC1 β-Cell proliferation Insulin S6K1 IRS-1 Obesity Insulin resistance β-Cell apoptosis T2D
  • 23. Milk: an mTORC1-driving signalling system Whey proteins CaseinsFast intestinal hydrolysis Slow intestinal hydrolysis Leucine mTORC1 Amino acids ββ-Cell Insulin                        Leu Insulin IGF-1  IRS1  Peripheral cell Leu mTORC1           4EBP1          S6K1 Cell growth  Cell proliferation
  • 24. Abundant whey protein-based dairy products of Western diet •  Whey protein concentrates (bodybuilding) •  Whey drinks •  Milk: whole milk, low fat milk, skim milk, buttermilk •  Cocoa drinks •  White coffee (Latte macchiato) •  Yogurts •  Ice creams •  Curd cheeses •  Milk chocolates and sweets •  Puddings •  Sausages
  • 25. Steady increase of leucine-rich milk proteins in Western Diets    Annual per capita cheese consumption in Germany [kg] 25   23 kg 2011 20   Widespread   distribu4on  of     refrigera4on   15   technology   10   5  3.9 kg1935 0   1935 ´50 ´55 ´60 ´65 ´70 ´75 ´80 ´85 ´90 ´95 2000 ´05 2010 Melnik BC et al. (2012)
  • 26. Does milk protein consumption induce insulin resistance? Milk consumption and insulin resistance
  • 27. S6K1-mediated insulin resistance by nutrient and amino acid overload Um SH et al. (2006)
  • 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)
  • 29. Amino acid-mTORC1-S6K1-mediated insulin resistance Um SH et al. (2006)
  • 30. Overactivation of S6K1 as a cause of human insulinresistance 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 ofIRS-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“ isurgently needed, which has primarily toappreciate tissue-specific alterations of insulinsignalling and not fasting parameters obtainedfrom 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 thebiochemical 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 thisstudy. 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. HOMAdata have been calculated from fasting serum levels of glucose and insulin and notfrom 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.        
  • 46.      The  biological  func@on  of  mammalian  milk  
  • 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 productsDiabetogenic effects by impaired Early onset of T2D by persistentβ-cell development and disturbed mTORC1-mediated β-cell proliferationpostnatal metabolic programming and early β-cell apoptosis
  • 48. Neurogenin3 expression: the critical step for thedevelopment 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 exceedsleucine-, 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
  • 54. Continued leucine-mediated β-cell proliferation and the risk of early replicative β-cell senescence
  • 55. Poten@al  risk  of  persistent  milk-­‐mediated  leucine-­‐ mTORC1-­‐signalling  in  the  pathogenesis  of  T2D  
  • 56. Postnatal β-cell mTORC1 hyperactivation by TSC2 ablation
  • 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 miceA 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 weeksthana high fat-low protein diet(39% fat, 17% casein, 43% carbohydrates),which was associated with a lower reductionof 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 repressor4E-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)
  • 68. mTORC1 controls SREBP1the master transcription factor of lipogenesis Porstmann T et al. (2009)
  • 69. Amino acids via mTORC1 increase lipin phosphorylationin 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)
  • 71. Molecular crosstalk between amino acids, mTORC1 and SREBP1 Porstmann T et al. (2009)
  • 72. Leucine stimulates PPARγ mRNA expression and adipose tissue increase in the ratZeanandin G et al. (2011)
  • 73. Regulation of PPARγ activity by mTORC1 and amino acids in adipogenesis Kim  JE  et  al.  (2004)   Kim JE et al. (2004)
  • 74. PPARγ is dependent on amino acid availabity and is regulated via mTORC1 Leucine Kim JE et al. (2004)
  • 75. Leucine: strongest activator of mTORC1-mediated 4EBP1-phosphorylation in adipocytes Lynch CJ et al. (2000)
  • 76. mTORC1 substrate S6K1 promotes differentiation of adipocytes from multipotent stem cells S6K1-/- miceNCD=normal chow dietHFD=high fat diet Carnevalli LS et al. (2010)
  • 77. mTORC1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storageActivation 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
  • 80. Epidemiological evidence:Dairy protein consumption increases serum IGF-1 levels                                        Crowe FL et al. (2009)
  • 81. Correlation between dairy protein intake and serum IGF-1 levels Crowe FL et al. (2009)
  • 82.                Correlation between serum IGF-1 levels and breast cancer- and prostate cancer risk
  • 83. All cancers express up-regulated IGF-1 receptor
  • 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 theassociation 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)
  • 87. Epidemiological evidence for dairy protein consumption and prostate cancer 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 adolescencehas been associated witha 3.2-fold increased risk of advanced prostate cancer Torfadottir JE et al. (2011)
  • 89. Milk consumption promotes the progression of prostate cancerMen with the highest versus lowest intake of whole milk were atan increased risk of prostate cancer progression Pettersson A et al. (2012)
  • 90. Milk stimulates growth of prostate cancer cells in vitroCow´s milk stimulated the growth of LNCaP prostate cancer cellsin each of 14 experimentsproducing 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)
  • 92. Milk signalling augments activated mTORC1 signalling pathways of prostate cancer cells &&&&&&&&& Induc&on! IGFH1% Insulin%%% %%%%%%%%MILK*%% % &&IR% %IGF1R% PI3K% IRS$1& RAS& Androgen$& precursors*& 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% MilkHmediated%mTORC1HoveracLvaLon%% promoLng%prostate%tumorigenesis%% Fig.&5& 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 riskfactor of breast cancer and ovarian cancer
  • 96. Relative increase in the consumption of milkand dairy proteins in Japan after World War II Milk and dairy products Li XM et al. (2003)
  • 97.  Correlation bewteen milk consumption and breast cancer mortality in Japan 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 riskfactor of breast cancer which correlates withincreased 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-inducedmammary 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 andtumor 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 birthweightMilk protein Increased Increasedintake during birthweight risk of breastpregnancy cancer
  • 106. Increased birthweight and breast cancer risk
  • 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.
  • 109. Does milk consumption promote or aggravate acne? Milk consumption and acne
  • 110.      Pathogenesis of acne Follicular hyperproliferationHyperproliferation and Follicular and peri-hyperplasia of sebaceous comedo follicular inflammationglands formation
  • 111. Common types of acneAcne comedonica Moderate acne Severe acnewith 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) USAretrospective 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 dietScience  326,  Dezember  2009  Evolu7on  of  Diseases  of  Modern  Environments  Charité  University  Medicine  Berlin,  Humbold  University,      
  • 120. Whey protein abusein the body building environment Whey acne      80  g  Whey  protein                    =  12  L  milk   Leucine + BCAAs Insulin + IGF-1 DHEAS mTORC1
  • 121. Acne cure by the paleo diet
  • 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)
  • 123. mTORC1: the convergence point of nutrient-signalling in acne Melnik BC (2012)
  • 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 activityHigh flux of milk-derived Consumption of less insulinotropicinsulinotropic amino acids amino acids derived from fish or meatcombined with high load of combined withhyperglycemic carbohydrates low glycemic carbohydratesWestern diet Paleolithic diet
  • 127. Milk-driven mTORC1 signalling andmTORC1-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.

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