Elsevier

Medical Hypotheses

Volume 72, Issue 6, June 2009, Pages 631-639
Medical Hypotheses

Milk – The promoter of chronic Western diseases

https://doi.org/10.1016/j.mehy.2009.01.008Get rights and content

Summary

Common chronic diseases of Western societies, such as coronary heart disease, diabetes mellitus, cancer, hypertension, obesity, dementia, and allergic diseases are significantly influenced by dietary habits. Cow’s milk and dairy products are nutritional staples in most Western societies. Milk and dairy product consumption is recommended by most nutritional societies because of their beneficial effects for calcium uptake and bone mineralization and as a source of valuable protein. However, the adverse long-term effects of milk and milk protein consumption on human health have been neglected. A hypothesis is presented, showing for the first time that milk protein consumption is an essential adverse environmental factor promoting most chronic diseases of Western societies. Milk protein consumption induces postprandial hyperinsulinaemia and shifts the growth hormone/insulin-like growth factor-1 (IGF-1) axis to permanently increased IGF-1 serum levels. Insulin/IGF-1 signalling is involved in the regulation of fetal growth, T-cell maturation in the thymus, linear growth, pathogenesis of acne, atherosclerosis, diabetes mellitus, obesity, cancer and neurodegenerative diseases, thus affecting most chronic diseases of Western societies. Of special concern is the possibility that milk intake during pregnancy adversely affects the early fetal programming of the IGF-1 axis which will influence health risks later in life. An accumulated body of evidence for the adverse effects of cow’s milk consumption from fetal life to childhood, adolescence, adulthood and senescence will be provided which strengthens the presented hypothesis.

Section snippets

Insulin and the insulin-like growth factor system

The insulin-like growth factor (IGF) system is essential for normal embryonic and postnatal growth, and plays an important role in the function of a healthy immune system, lymphopoiesis, myogenesis and bone growth among other physiological functions. Growth hormone (GH) and IGFs play an important role in growth and tissue homeostasis. GH secreted by the anterior pituitary binds to GH receptor, expressed on most peripheral cells of the body. In peripheral tissues and predominantly in the liver,

Milk and milk protein consumption increase IGF-1 serum levels

Milk is a complex, bioactive substance honed by evolution to promote growth and development of the infant mammal. Cow’s milk and dairy products derived from milk are widely consumed by children and adults of Western societies well after the age of weaning. It is important to note that cow’s milk contains active IGF-1 (4–50 ng/ml) and IGF-2 (40–50 ng/ml) [3], [4]. IGF-signalling belongs to the canonical pathways and networks regulated by estrogen and placental GH in the bovine mammary gland. Cows

The insulinotropic effect of milk and milk products

Fermented and non-fermented milk products give rise to insulinaemic responses far exceeding what could be expected from their low glycaemic indexes (GI). Despite low GIs of 15–30, milk products produce three to sixfold higher insulinaemic indexes (II) of 90–98 [17]. A large and similar dissociation of the GI and II exists for both whole milk (GI: 42 ± 5; II: 148 ± 14) and skim milk (GI: 37 ± 9; II: 140 ± 13) [18]. It has been suggested that some factor within the protein fraction of milk is responsible

Differential induction of insulin and IGF-1 by milk protein fractions

The major protein fractions of cow’s milk is casein (80%), the remaining 20% are whey proteins. Both, whey and casein contain specific proteins and peptides that may have growth stimulating effects. The effect of whey and casein fractions of milk on fasting concentrations of IGF-1 and insulin has been examined in 57 eight-year-old boys who received over seven days either casein or whey protein fractions with protein amounts of casein or whey similar to the content of 1.5 l skim milk. In the

Insulin induces hepatic synthesis and secretion of IGF-1

The main source of circulating IGF-1 is considered to be the liver. A study of seven insulin-dependent diabetic patients in whom insulin was withheld for 12 h received insulin infusions (1.6 mU insulin/kg/min) after an overnight fasted state. Serum IGF-1, but not IGFBP-3, significantly increased during the insulin infusion, whereas hepatic IGFBP-1 synthesis was reduced [26]. Mean serum baseline levels of IGF-1 in arterial blood (166 μg/l) and hepatic vein (160 μg/l) blood increased during the 180 

The impact of milk consumption on fetal growth

Both IGF-1 and IGF-2 are expressed in fetal tissues from the earliest stage of pre-implantation to the final phase of tissue maturation before birth. IGF-2 is the primary growth factor supporting embryonic growth, with IGF-1 increasing in importance later in gestation. Concentrations of IGF-1 in the fetus are affected by nutrient supply to the fetus and nutrient-sensitive hormones [27]. Insulin positively regulates IGF-1 levels [28]. In industrialized countries, one of 10 newborns is affected

Early programming of the GH-IGF-1 axis

The GH-IGF-1 axis is closely related to feeding in the newborn [37]. More recent data point to an early programming of the IGF-1 axis within the first months of live. In early pregnancy maternal endocrine IGF-1 programs the placenta for increased functional capacity throughout gestation [38]. IGFs play a critical role in fetal and placental growth throughout gestation [27], [39]. Increased maternal milk consumption during pregnancy enhances the nutrient supply for the fetus by an enlarged

Milk consumption shifts the GH-IGF-1 axis in pre-pubertal children

After a month of drinking 710 ml of ultra-heat treated whole milk daily, 10–11-year-old Mongolian children, previously not used to milk consumption, had a higher mean plasma level of IGF-1 and higher ratio of IGF-1/IGFBP-3 [41]. The mean serum IGF-1 levels were raised in the children after 4 weeks of milk consumption by 23.4% from mean pre-treatment values of 291–358 ng/ml [41]. There is good evidence that milk consumption shifts the human intrinsic IGF-1 axis to unusual high levels.

Milk consumption and linear growth

Over the last centuries, body height significantly accelerated. Milk intake is the best source for utilization of calcium for bone growth and mineralization and is positively associated with IGF-1 serum levels [15]. Milk consumption during pregnancy is associated with increased infant size at birth [29]. During a four-week intervention with daily milk intake of 710 ml, Mongolian children experienced a rapid linear growth (the equivalent of 12 cm/year). Girls grew a mean 1.1 + 0.2 cm and boys 1.0 + 0.2 

Effect of IGFs and insulin on adreno-gonadal maturation and onset of puberty

The GH–IGF-1 axis plays an important role for the ACTH-dependent production of dehydroepiandrosterone sulphate (DHEAS) of the human adrenal gland [44]. IGF-1 is involved in ovarian androgen synthesis and has been implicated in the pathogenesis of ovarian hyperandrogenism and polycystic ovary syndrome (PCOS) [45]. IGF-1 serum levels are increased in patients with PCOS who exhibit insulin resistance, anovulation, hyperandrogenism with acne and hirsutism. Proliferation and differentiation of adult

Milk consumption, IGF-1 serum levels and acne

Acne is regarded as an androgen-dependent disease of the pilosebaceous follicle. Its course, however, corresponds less closely to plasma androgen levels than it does to GH and IGF-1 levels [53]. Significantly increased serum levels of IGF-1 have been observed in women with post-adolescent acne as well as adult acne patients [54], [55]. In women, the total number of acne lesions correlated with serum IGF-1 levels. In Western societies, acne is a nearly universal disease afflicting 79–95% of the

Endocrine disorders associated with increased IGF-1 serum levels and acne

In pre-pubertal girls with premature adrenarche significantly higher ACTH-stimulated 17-hydroxy-pregnenolone and DHEA serum levels, high IGF-1, and low IGFBP-1 have been reported [62]. It is remarkable, that premature pubarche shares many clinical characteristics with PCOS [62]. PCOS is associated with increased serum levels of IGF-1 and DHEAS, hyperinsulinemia, insulin resistance, acne and hirsutism [63]. Twofold elevated serum levels of free IGF-1 have been detected in women with PCOS [63].

Milk consumption and obesity

IGF-1 is required for terminal differentiation of pre-adipocytes into adipocytes [65], [66]. Milk consumption during pregnancy increased infant size and birth weight [29], [30]. Data from the Danish National Birth Cohort (n = 50,117) demonstrate a significant association between increase in birth weight and quantified intakes of protein from dairy products [29].Umbilical cord serum IGF-1 concentrations were higher in LGA newborns compared to AGA and SGA newborns [34]. Umbilical cord serum IGF-1

Postnatal IGF-1 axis, diabetes mellitus and hypertension

The IGF-1 axis may be programmed by diet early in infancy [40]. An inverse relation between IGF-1 levels during the first months of life and IGF-1 levels in adulthood could be observed in 109 infants of the observational Copenhagen cohort study [40]. Low levels of IGF-1 in the postnatal period are associated with high IGF-1-levels in adolescence. Low levels of IGF-1 are reported in SGA newborn infants [34]. Low birth weight is a recognized risk factor for the development of type 2 diabetes and

Milk, insulin, IGF-1 and cancer

IGF-1 is a known mitogenic hormone that stimulates growth, differentiation and metabolism in a variety of cell types [81]. IGF-1 participates in the regulation of the cell cycle, inhibiting the processes of apoptosis and stimulating cell proliferation. IGF-1 is a potential tumour promoter [82]. Several studies demonstrated a link between increased IGF-1 serum levels with increased risk of breast, prostate, colorectal, and lung cancer [83]. High expression of IGF1Rs has been detected in the

Milk consumption in pregnancy, birth weight and risk of breast cancer

Milk consumption during pregnancy increases maternal IGF-1 serum levels, birth weight and height of the newborn [29], [42], [43], all known risk factors of breast cancer [98], [99]. The intrauterine environment might contribute to the predisposition of women for breast cancer in adulthood [100]. The responsible in-utero-mechanism has been linked to IGF-1 [101]. Thus, the environmental breast cancer-promoting factor of Western societies could be associated with milk-induced IGF-signalling during

Milk, IGF-1 and cardiovascular disease

The association between milk consumption and mortality from ischemic heart disease has been suggested in this journal 25 years ago [106]. A linear correlation between the consumption of unfermented milk proteins and male mortality of coronary heart disease has been demonstrated [107]. Animal models have shown that IGF-1 is involved in stimulating atherosclerosis [108], [109]. IGF1Rs are abundant in vascular smooth muscle cells and factors that stimulate atherosclerosis, such as angiotensin II

IGF-1 signalling and neurodegenerative diseases

The major risk factor for the development of neurodegenerative disease is aging [112]. Mechanistic links between the aging process and toxic protein aggregation, a common hallmark of neurodegenerative diseases, has been revealed. Lifespan is regulated by at least three different mechanisms, one of which is the insulin/IGF-1 signalling pathway. The insulin-IGF-1 pathway is the major candidate to link aging, proteotoxicity and late-onset neurodegenerative disease [113], [114]. It has been

The IGF-axis and allergic and autoimmune disorders

The thymus is the only organ specialized in the establishment of immunological self-tolerance and stands at the crossroads between the immune and neuroendocrine systems [116]. The neuroendocrine system regulates the process of T-cell differentiation from the very early stages. T lymphocytes undergo in the thymus a complex educative process that establishes central T-cell self-tolerance of neuroendocrine principle. Neuroendocrine self-antigens correspond to peptide sequences that have been

Discussion and hypothesis

Our “inborn belief” of the beneficial effect of cow’s milk in human nutrition is challenged. Humans are the only species on earth allowed to consume milk, an evolutionary designed sophisticated growth-signalling system, lifelong after weaning. Cow’s milk consumption and most likely other dairy products have an enormous impact on the human GH/insulin/IGF-1 axis, disturbing most sensitive hormonal regulatory signalling networks, interfering with IGF1R-signalling from fetal life to senescence (

References (118)

  • H.-C. Lo et al.

    Relation of cord serum levels of growth hormone, insulin-like growth factors, insulin-like growth factor binding proteins, leptin, and interleukin-6 with birth weight, birth length, and head circumference in term and preterm neonates

    Nutrition

    (2002)
  • A.N. Sferruzzi-Perri et al.

    Maternal insulin-like growth factor-II promotes placental functional development via the type 2 IGF receptor in the guinea pig

    Placenta

    (2008)
  • C.A. Adebamowo et al.

    Milk consumption and acne in teenaged boys

    J Am Acad Dermatol

    (2008)
  • S.M. Rudman et al.

    The role of IGF-I in human skin and its appendages: morphogen as well as mitogen?

    J Invest Dermatol

    (1997)
  • S. Blüher et al.

    Insulin-like growth factor-I, growth hormone and insulin in white adipose tissue

    Best Pract Res Clin Endocrinol Metab

    (2005)
  • H. Hauner et al.

    Adipogenic activity in sera from obese children before and after weight reduction

    Am J Clin Nutr

    (1989)
  • M. Wabitsch et al.

    The role of growth hormone/insulin-like growth factors in adipocyte differentiation

    Metabolism

    (1995)
  • A. Falorni et al.

    Serum levels of type I procollagen C-terminal peptide, insulin-like growth factor-I (IGF-I), and IGF binding protein-3 in obese children and adolescents: relationship to gender, pubertal development, growth, insulin, and nutritional status

    Metabolism

    (1997)
  • G. Andronico et al.

    Insulin-like growth factor-1 and pressure load in hypertensive patients

    Am J Hypertens

    (1996)
  • G. Fürstenberger et al.

    Insulin-like growth factors and cancer

    Lancet

    (2002)
  • P.G. Moorman et al.

    Consumption of dairy products and the risk of breast cancer: a review of the literature

    Am J Clin Nutr

    (2004)
  • K.B. Michels et al.

    Birthweight as a risk factor for breast cancer

    Lancet

    (1996)
  • F. Xue et al.

    Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence

    Lancet Oncol

    (2007)
  • A. Denley et al.

    The insulin receptor isoform exon 11- (IR-A) in cancer and other diseases: a review

    Horm Metab Res

    (2003)
  • J.W. Blum et al.

    Insulin-like growth factors (IGFs), IGF binding proteins, and other endocrine factors in milk: role in the newborn

  • G.L. Francis et al.

    Insulin-like growth factors 1 and 2 in bovine colostrum. Sequences and biological activities compared with those of a potent truncated form

    Biochem J

    (1988)
  • J. Cadogan et al.

    Milk intake and bone mineral acquisition in adolescent girls. A randomised, controlled intervention trial

    Brit Med J

    (1997)
  • J. Ma et al.

    Milk-intake, circulating levels of insulin-like growth factor-I, and risk of colorectal cancer in man

    J Natl Cancer Inst

    (2001)
  • E. Giovannucci et al.

    Nutritional predictors of insulin-like growth factor-I and their relationships to cancer in man

    Cancer Epidemiol Biomarkers Prev

    (2003)
  • M.D. Holmes et al.

    Dietary correlates of plasma insulin-like growth factor-I and insulin-like growth factor binding protein 3 concentrations

    Cancer Epidemiol Biomarkers Prev

    (2002)
  • C. Hoppe et al.

    High intakes of skimmed milk, but not meat increase serum IGF-I and IGFBP-3 in eight-year-old boys

    Eur J Clin Nutr

    (2004)
  • I.S. Rogers et al.

    Cross-sectional associations of diet and insulin-like growth factor levels in 7- to 8-year-old children

    Cancer Epidemiol Biomarkers Prev

    (2005)
  • Esterle L, Sabatier J-P, Metz FG, Walrant-Debray O, Guaydier-Souquières G, Jehan F et al. Milk, rather than other...
  • T. Norat et al.

    Diet, serum insulin-like growth factor-I and IGF-binding protein-3 in European women

    Eur J Clin Nutr

    (2007)
  • G. Hoyt et al.

    Dissociation of the glycaemic and insulinaemic responses to whole and skimmed milk

    Br J Nutr

    (2005)
  • M.C. Gannon et al.

    The serum insulin and plasma glucose responses to milk and fruit in type 2 (non-insulin-dependent) diabetic patients

    Diabetologica

    (1986)
  • E.H. Liljeberg et al.

    Milk as a supplement to mixed meals may elevate postprandial insulinaemia

    Eur J Clin Nutr

    (2001)
  • C. Hoppe et al.

    Cow’s milk and linear growth in industrialized and developing countries

    Ann Rev Nutr

    (2006)
  • Hoppe C, Molgaard C,Vaag A, Michaelsen KF. The effect of seven-day supplementation with milk protein fractions and milk...
  • P.L. Brubaker et al.

    Direct and indirect mechanisms regulating secretion of glucagon-like peptide-1 and glucagon-like peptide-2

    Can J Physiol Pharmacol

    (2003)
  • K. Brismar et al.

    Effect of insulin on the hepatic production of insulin-like growth factor binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes

    J Clin Endocrinol Metab

    (1994)
  • C. Gicquel et al.

    Hormonal regulation of fetal growth

    Horm Res

    (2006)
  • A.L. Fowden et al.

    Endocrine mechanisms of intrauterine programming

    Reproduction

    (2004)
  • C.A. Mannion et al.

    Association of low intake of milk and vitamin D during pregnancy with decreased birth weight

    Can Med Assoc J

    (2006)
  • S.W. Yang et al.

    Relationship of insulin-like growth factor-I, insulin-like growth factor binding protein-3, insulin, growth hormone in cord blood and maternal factors with birth height and birthweight

    Pediatr Int

    (2000)
  • C. Chiesa et al.

    Ghrelin, leptin, IGF-1, IGFBP-3, and insulin concentrations at birth: Is there a relationship with fetal growth and neonatal anthropometry?

    Clin Chem

    (2008)
  • M. Akcakus et al.

    The relationship among intrauterine growth, insulin-like growth factor-I (IGF-I), IGF-binding protein-3, and bone mineral status in newborn infants

    Am J Perinatol

    (2006)
  • K.K. Onk et al.

    Pregnancy insulin, glucose, and BMI contribute to birth outcomes in nondiabetic mothers

    Diabetes Care

    (2008)
  • A.L. Ogilvy-Stuart et al.

    Insulin, insulin-like growth factor-I (IGF-I), IGF-binding protein-1, growth hormone, and feeding in the newborn

    J Clin Endocr Metab

    (1998)
  • A.N. Sferruzzi-Perri et al.

    Early pregnancy maternal endocrine insulin-like growth factor-I programs the placenta for increased functional capacity throughout gestation

    Endocrinology

    (2007)
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