WO2010119088A2 - Lait et produits lactés modifiés pour présenter un indice insulinémique réduit et/ou une activité mitogène réduite - Google Patents

Lait et produits lactés modifiés pour présenter un indice insulinémique réduit et/ou une activité mitogène réduite Download PDF

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WO2010119088A2
WO2010119088A2 PCT/EP2010/054937 EP2010054937W WO2010119088A2 WO 2010119088 A2 WO2010119088 A2 WO 2010119088A2 EP 2010054937 W EP2010054937 W EP 2010054937W WO 2010119088 A2 WO2010119088 A2 WO 2010119088A2
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milk
igf
insulin
activity
reduce
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WO2010119088A3 (fr
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Bodo Melnik
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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/20—Dietetic milk products not covered by groups A23C9/12 - A23C9/18
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
    • A23C9/1203—Addition of, or treatment with, enzymes or microorganisms other than lactobacteriaceae
    • A23C9/1209—Proteolytic or milk coagulating enzymes, e.g. trypsine
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
    • A23C9/00—Milk preparations; Milk powder or milk powder preparations
    • A23C9/14—Milk preparations; Milk powder or milk powder preparations in which the chemical composition of the milk is modified by non-chemical treatment
    • A23C9/148—Milk preparations; Milk powder or milk powder preparations in which the chemical composition of the milk is modified by non-chemical treatment by molecular sieve or gel filtration or chromatographic treatment
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/40—Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • Milk and milk-based products modified to exhibit a reduced insulinemic index and/or reduced mitoqenic activity
  • the present invention relates to processes for treating milk and milk products obtainable by the treatment which will not be able to induce insulin resistance and/or exhibit a reduced insulinemic index and/or reduced mitogenic activity
  • 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.
  • milk intake during pregnancy adversely affects the early fetal programming of the IGF-I 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.
  • GH-IGF-1-axis somatotropic axis
  • a modified cow milk or milk of another milk-giving species should be used which has by treatment not the ability to induce insulin resistance, i.e., this modified milk is not able to interfere with the GH-IGF-1-axis and will not increase human GH, insulin and IGF-I serum levels.
  • Special targets for inactivation are bovine alpha- Lactalbumin and alpha-Lactalbumin of other species used for milk production for humans.
  • Insulin and the insulin-like growth factor system are 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, GH induces the synthesis and secretion of the 7.65 kDa polypeptide hormone IGF-I, the mediator of the growth stimulating activity of GH.
  • IGFBP-3 IGF-binding protein-3
  • IGFBP-2 IGF-binding protein-3
  • IGFBP-2 IGF-binding protein-3
  • IGFlR IGF-1-receptor
  • IR insulin receptor
  • IGF-2 binds to IGF-2-receptor (IGF2R), a scavenger receptor down-regulating IGF-2.
  • IGF-2 is also able to bind to IGFlR.
  • Insulin primarily binds to IR-A and IR-B, but also binds with lower affinity to IGFlR.
  • IGF-I and IGF-2 bind to IR with lower affinity ( Figure 1).
  • IGFlR signal transduction is mediated primarily by the activation of the Ras-Raf-MAP kinase pathway and the phosphoinositide 3-kinase (PI3K)/Akt pathway.
  • IGF-I acts a strong mitogen inducing cell growth and proliferation, but inhibits apoptosis [I].
  • the IR-B isoform is the form best known for the classic metabolic responses induced upon insulin binding and this isoform has low affinity for IGFs [I].
  • the IR-A isoform arises from alternative splicing of exon 11 encoded by the IR gene. Activation of the IR-A by insulin or IGF-2 leads to mitogenic responses similar to those described for IGFlR. Increased signaling via IR-A has been associated with the development of cancer [2]. In this regard, insulin and IGF-2 signal transduction via IR-A and IGF-I signaling via IGFlR induce and amplify mitogenic responses (Figure 1).
  • 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-I (4-50 ng/ml) and IGF-2 (40-50 ng/ml) [3, 4].
  • IGF-signaling belongs to the canonical pathways and networks regulated by estrogen and placental GH in the bovine mammary gland. Cows treated with recombinant bovine GH to improve milk yield showed increased levels of IGF-I in the milk [4]. High levels of IGF-I are still detectable after pasteurization and homogenization of milk [5]. Intriguingly, bovine and human IGF-I share the same amino acid sequences and therefore bovine IGF-I can bind to the human IGFlR [6].
  • IGFs in milk can survive digestion and remain bioactive in the serum of milk consumers.
  • Intestinal absorption of growth factors in milk may be increased by Western diet which is high in wheat products and potatoes. It has been recognized that wheat-derived gluten and potato-derived glycoalkaloids perturb and increase intestinal permeability resulting in increased intestinal protein absorption [6a, 6b, 6c].
  • 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 to 30, milk products produce three- to sixfold higher insulinaemic indexes (II) of 90-98 [17].
  • II insulinaemic indexes
  • casein 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-I 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 I skim milk.
  • serum IGF-I increased by 15%, whereas there was no change in fasting insulin.
  • whey group fasting insulin increased by 21%, with no change in IGF-I [23, 24, 24a].
  • whey proteins induce high GIP responses of enteroendocrine intestinal L-cells promoting insulin secretion of pancreatic beta-cells [25a, 25b]. GIP receptors are also expressed on adipocytes and stimulate adipogenesis [25c]. The whey protein-GIP signaling due to milk consumption will thus increase pancreatic insulin secretion and GIP-mediated adipocyte proliferation and differentiation promoting the development of obesity [25c]. Whey proteins further induce cholecystokinin (CCK) from intestinal I-cells [Hall WL et al. Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite. Br J Nutr 2003; 89: 239].
  • CCK cholecystokinin
  • a typical "Western" combination diet composed of milk proteins and food with high glycaemic index will have potentiating effects on serum insulin, IGF-I, GLP-I and GIP- levels thereby promoting anabolic signaling pathways involved in mitogenesis and antiapoptosis.
  • Insulin induces hepatic synthesis and secretion of IGF-I
  • the main source of circulating IGF-I is considered to be the liver.
  • Mean serum baseline levels of IGF-I in arterial blood (166 ⁇ g/l) and hepatic vein (160 ⁇ g/l) blood increased during the 180 min of insulin infusion to 183 ⁇ g/l and 185 ⁇ g/l, respectively [26].
  • insulin infusion raised serum IGF-I levels by approximately 13%.
  • IGF-I 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-I increasing in importance later in gestation.
  • Concentrations of IGF-I in the fetus are affected by nutrient supply to the fetus and nutrient-sensitive hormones [27]. Insulin positively regulates IGF-I levels [28].
  • one of 10 newborns is affected with fetal macrosomia which has been associated with an increased risk of developing diabetes type 2 later in life. Milk consumption during pregnancy has been associated with a higher birth weight of the offspring [29, 30].
  • Levels of IGF-I and IGFBP-3 appear to be regulated by several factors, such as insulin, GH and maternal factors [31].
  • Levels of IGF-I in cord sera of newborns small for gestational age (mean 48.7 ng/ml) were lower than those of newborns appropriate for gestational age (AGA) (56.4 ng/ml).
  • AGA adultborns large for gestational age (LGA) exhibited the highest IGF-I cord sera levels (96.1 ng/ml) [31].
  • a recent study showed significantly higher insulin, leptin, IGFBP- 3, and glucose concentrations in asymmetric LGA newborns than in symmetric LGA and AGA newborns [32].
  • Macrosomic neonates of diabetic mothers have significantly increased aortic intima-media thickness with higher serum IGF-I, IGFBP-3 and leptin concentrations than those of controls [33].
  • Umbilical cord serum IGF-I levels were correlated significantly with the IGF-I concentrations of the mothers [34].
  • Umbilical cord serum levels of free IGF-I, total IGF-I, IGFBP-2 and leptin have been demonstrated as predictors of birth weight [35].
  • Recently, normal variations in maternal glycaemia on birth size and birth outcomes has been investigated in nondiabetic mothers [36].
  • the GH-IGF-I axis is closely related to feeding in the newborn [37]. More recent data point to an early programming of the IGF-I axis within the first months of live. In early pregnancy maternal endocrine IGF-I 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 placenta. In the guinea pig administration of IGF-I during early pregnancy increased placental transport of glucose and amino acids and increased placental and fetal weights [38].
  • the breastfed infants showed an increased IGF-I level of 328 ⁇ 78.5 in comparison to decreased IGF-I levels of 292.9 ⁇ 95.0 of not breast-fed adolescents of the same age [40].
  • IGF-I axis is programmed early in life [40].
  • milk protein consumption during pregnancy is associated with increased serum levels of IGF-I and postprandial hyperinsulinaemia, a milk protein-mediated shift of the IGF-I axis to higher levels has to be expected early in pregnancy.
  • One of the first effects of milk consumption during early pregnancy might increase maternal IGF-I levels which program the placenta for increased functional capacity throughout gestation thereby increase the risk of fetal macrosomia and other IGF-I- dependent diseases [38].
  • the GH-IGF-I axis plays an important role for the ACTH-dependent production of dehydroepiandrosterone sulphate (DHEAS) of the human adrenal gland [44].
  • DHEAS dehydroepiandrosterone sulphate
  • IGF-I is involved in ovarian androgen synthesis and has been implicated in the pathogenesis of ovarian hyperandrogenism and polycystic ovary syndrome (PCOS) [45].
  • IGF-I serum levels are increased in patients with PCOS who exhibit insulin resistance, anovulation, hyperandrogensism with acne and hirsutism. Proliferation and differentiation of adult testicular Leydig cells is the prerequisite for the increase of circulating plasma androgens during puberty.
  • IGF-I is an essential local mediator of testicular steroidogenesis. In human testicular cell cultures, IGF-I stimulated testosterone secretion and cell proliferation, whereas apoptosis was inhibited [46]. Both insulin and leptin are thought to accelerate the timing of pubertal onset and to up-regulate the tempo of pubertal progression [47, 48]. The insulin sensitizing agent metformin decreases elevated serum IGF-I levels in patients with PCOS [49]. Girls with precocious pubarche and low birth weight reveal increased IGF-I serum levels and insulin resistance which leads to rapid progression of puberty. These girls are predisposed to develop PCOS [50].
  • Metformin treatment (425 mg/day) over two years of eight-year-old girls with precocious pubarche and low birth weight prevented the onset of early puberty by 0.4 years and significantly decreased serum levels of IGF-I, fasting insulin, DHEAS and testosterone [51].
  • 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-I levels [53]. Significantly increased serum levels of IGF-I 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-I levels. In Western societies, acne is a nearly universal disease afflicting 79 to 95% of the adolescent population. In men and women older than 25 years, 40% to 54% have some degree of facial acne, and clinical facial acne persists into middle age in 12% of women and 3% of men [56].
  • the IGF-I axis may be programmed by diet early in infancy [40]. An inverse relation between IGF-I levels during the first months of life and IGF-I levels in adulthood could be observed in 109 infants of the observational Copenhagen cohort study [40]. Low levels of IGF-I in the postnatal period are associated with high IGFl-levels in adolescence. Low levels of IGF-I are reported in SGA newborn infants [34]. Low birth weight is a recognized risk factor for the development of type 2 diabetes and hypertension in adulthood [74, 75].
  • IGF-I receptors are up- regulated by angiotensin II [78].
  • IGF-I mRNA and protein expression and IGF-I plasma levels in hypertensive patients have been related to pressure load [79, 80].
  • mice indicate a significant link between early postnatal diet, somatotropic development, and specific late onset diseases in mice.
  • IGF-I may play a role in modulating hypothalamic stimulation of the developing somatotropic function [8Oa].
  • IGF-I is a known mitogenic hormone that stimulates growth, differentiation and metabolism in a variety of cell types [81]. IGF-I participates in the regulation of the cell cycle, inhibiting the processes of apoptosis and stimulating cell proliferation. IGF-I is a potential tumor promoter [82]. Several studies demonstrated a link between increased IGF-I serum levels with increased risk of breast, prostate, colorectal, and lung cancer [83]. High expression of IGFlRs has been detected in the majority of human cancers. Several studies have confirmed that IGF-I serum levels are related to premenopausal breast density, one of the strongest known breast cancer risk factors believed to represent epithelial and stromal proliferation [84-86].
  • a higher risk for cervical, ovarian and endometrial cancer is related to high IGF- 1 levels in post- and premenopausal women [87].
  • Plasma IGF-I levels and inherited variation in IGF-I have been implicated to be a risk factor in prostate carcinoma [88-90].
  • a high intake of dairy products and calcium has been associated with an increased risk of prostate cancer in a recent meta-analysis [91].
  • IGF-I and insulin act through the tyrosine kinase growth factor signaling cascade enhancing tumor cell proliferation [92].
  • Higher serum IGF-I in older men has been associated with increased risk of cancer death, independent of age, adiposity, lifestyle, and cancer history [92a].
  • IGF-1-dependent T-cell maturation in the fetal thymus might affect the immune system's capacity to handle anti-tumor mechanisms later in life. Thus, fetal macrosomia could have a fatal outcome later in life.
  • Individuals affected by genetic variations in the expression of IGF-I resulting in high IGF- 1 serum levels are at increased risk for cancer. Absence of the IGFl 19-CA repeat allele has been associated with high IGF-I levels during oral contraceptive use in nulliparous women in four different ethnic groups [102]. The IGFl 19-CA repeat allele modifies IGF-I levels, breast volume and possibly early-onset breast cancer risk after hormone exposure in young high- risk women [103, 104].
  • IGF-I is involved in stimulating atherosclerosis [108, 109].
  • IGFlRs are abundant in vascular smooth muscle cells and factors that stimulate atherosclerosis, such as angiotensin II up-regulate IGFlR expression [HO].
  • IGF-I secreted by activated monocytes can stimulate smooth muscle cell proliferation and extracellular matrix synthesis which lead to enlargement of the developing atheroma [111]. It is conceivable, that the relative small IGF-I polypeptide diffuses from the plasma into the early atheromatous lesions. In this regard, milk-derived IGF-I augments local IGF-1-dependent atherogenic effects.
  • 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 signaling pathway. The insulin-IGF-1 pathway is the major candidate to link aging, proteotoxicity and late-onset neurodegenerative disease [113, 114]. It has been suggested that reducing insulin-IGF-1 signaling in the brain will enable cells to maintain the activity of protein quality-control mechanisms and clearance capabilities to a later age, thereby postponing the onset of neurodegenerative diseases [113].
  • Prolonged milk-induced disturbance of the insulin- IGF-1 pathway has to be considered as a possible accelerator of neurodegenerative disorders.
  • circulating IGF-I is able to cross the blood-brain barrier and enter into the brain.
  • 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 highly conserved throughout the evolution of one given family [116].
  • IGF-2 thymic cortex and thymic "nurse” cells
  • IGF-I thymic macrophages
  • insulin medulla
  • the blockade of thymic IGF-mediated signaling at the level of IGF ligands or IGFRs interferes with the early stages of T cell differentiation in fetal thymic organ cultures [117].
  • IGF-I stimulates thymus growth and T cell proliferation and development.
  • Thymocytes pre-T cells express IGFRl and IGFR2.
  • IGF-mediated signaling between stromal cells (thymic epithelial cells, macrophages) and immature T cells during their differentiation in the thymus [117].
  • stromal cells thymic epithelial cells, macrophages
  • IGF-I activates the PI3K-pathway, involved in the activation of cell proliferation and inhibition of apoptosis [1, 82]. Consumption of boiled farm milk during pregnancy was positively associated with increased immunoglobulin E serum levels to cow ' s milk and other food allergens [118].
  • the milk-induced maternal increase of the insulin-IGF-1 signaling might shift the insulin-IGF-1 axis in the fetal thymus, thereby damaging proper apoptosis of allergy- and autoimmune-prone T-cells explaining the co-appearance of atopic and autoimmune diseases later in life.
  • breast-fed humans have significantly lower serum IGF-I levels than those fed on a cow milk based formula [40].
  • the consumption of milk and milk products in pregnancy would be a good explanation for the dominating maternal effect in the transmission of atopic diseases.
  • Growth hormone (somatropin, GH) is a peptide hormone that stimulates growth and cell reproduction. Growth Hormone induces the release of IGF-I and insulin. By its action, growth hormone induces insulin resistance. Therefore, it is suspected to be involved in the dysregulation of insulin and IGF-I during consumption of milk.
  • Ghrelin is a 28 amino acid peptide wherein the Ser-3 residue is n-octanoylated (Nature 402 (1999) 656-660). Ghrelin is predominantly produced in the human stomach. In the anterior pituitary somatotroph cells, ghrelin binds to GH secretagogue receptor, called GHS receptor type Ia. In this acylated form, ghrelin stimulates the secretion of GH. The deacylated peptide is inactive. Octanoyl is only one possible side chain. GH induces insulin resistance in humans and mammals for physiologic growth. Ghrelin has recently been detected in human breast milk, cow milk and goat milk (Aydin S et al.
  • Ghrelin is present in human colostrums, transitional and mature milk. Peptides 27 2006; 878-882).
  • the bovine GHRL gene has recently been characterized (Colinet F et al. Molecular characterization of bovine GHRL gene. Archiv Tierzucht 2009; 52:79-84).
  • Bovine ghrelin is a peptide of 27 amino acids. During peak of lactation, plasma concentrations of bovine ghrelin and GHare greater in samples from high genetic merit Holstein-Friesian cows (Roche JR et al. Short communication : genetic selection for milk production increases plasma ghrelin in dairy cows. J Dairy Sci 2006; 89: 3471-3475).
  • bovine ghrelin determines the level of ghrelin in cow milk.
  • Bovine ghrelin has been detected recently in cow milk (Karatas F et al. Ghrelin and orotic acid increased in subclinical mastitis. Arch Physiol Biochem 2008; 114: 178-182).
  • Formula fed infants had higher serum ghrelin levels (2654.86 versus 2132.96 pg/ml) and higher IGF-I levels (3.73 versus 3.15 ng/ml) in comparison to breast-fed infants (Savino F et al. Ghrelin, leptin and IGF-I levels in breast-fed and formula fed infants in the first years of life.
  • bovine ghrelin is suspected to be the cause of increased human ghrelin levels which increase human pituitary GHsecretion and thus induce insulin resistance with hyperinsulinemia and increased IGF-I serum levels, unwanted adverse effects on human health.
  • Bovine betacellulin is found in substantial amounts in cow milk (1 930 ng/liter) and is quite stable and survives the pasteurization process and is even found in high concentrations in cheese. BTC passes the gut barrier and enters the systemic circulation to promote growth and most likely increases insulin secretion and beta-cell hyperplasia of pancreatic islet cells.
  • Betacellulin a member of the epidermal growth factor (EGF) family, was purified from the conditioned medium of a cell line derived from mouse pancreatic beta cell tumors. Its primary translational product is composed of 178 amino acid residues, which contains a signal sequence, transmembrane and cytoplasmic domains in addition to the EGF-like domain.
  • Mature betacellulin is composed of 80 amino acid residues with extensive glycosylation and has a molecular weight of about 32 kDa. Betacellulin expresses in alpha, beta, and duct cells in normal adult pancreas, and converts rat pancreatic amylase-secreting cells (AR42J cells) to insulin expressing cells together with activin. In addition, PDX-I, one of the transcriptional factors for beta cells, induces insulin gene expression in a TCl cells in the presence of Betacellulin.
  • Betacellulin also has the potential for the growth of a rat insulinoma cell line, INS-I cells, and the recombinant human betacellulin accelerates the improvement of glucose tolerance in mice with diabetes induced by selective alloxan perfusion. According to these observations, Betacellulin is thought to be necessary for differentiation and/or growth of the pancreatic beta cells.
  • betacellulin binds to Erbl and Erb4-receptor homodimers and all Erb receptor heterodimers and thus is an important nutritional stimulus of Erb- dependent carcinoma cells.
  • Alpha-lactalbumin The key element
  • Alpha-lactalbumin is an important whey protein in cow's milk ( ⁇ 1 g/l), and is also present in the milk of many other mammalian species. In primates, alpha-lactalbumin expression is upregulated in response to the hormone prolactin and increases the production of lactose. Alpha-lactalbumin forms the regulatory subunit of the lactose synthase (LS) heterodimer and ⁇ -1,4- galactosyltransferase (beta4Gal-Tl) forms the catalytic component. Together, these proteins enable LS to produce lactose by transferring galactose moieties to glucose.
  • LS lactose synthase
  • beta4Gal-Tl ⁇ -1,4- galactosyltransferase
  • alpha-lactalbumin strongly binds calcium and zinc ions and may possess bactericidal or antitumor activity.
  • a folding variant of alpha-lactalbumin, called HAMLET likely induces apoptosis in tumor and immature cells.
  • alpha-lactalbumin When formed into a complex with GaI-Tl, a galactosyltransferase, alpha-lactalbumin enhances the enzyme's affinity for glucose by about 1000 times, and inhibits the ability to polymerize multiple galactose units. This gives rise to a pathway for forming lactose by converting GaI-TI to lactose synthase.
  • the molecular weight is 14178 Da, and the isoelectric point is between 4.2 and 4.5.
  • beta-lactoglobulin does not have any free thiol group that can serve as the starting point for a covalent aggregation reaction. As a result, pure alpha-lactalbumin will not form gels upon denaturation and acidification.
  • Alpha-lactalbumin is hydrolyzed in the intestine and induces the synthesis of glucose-dependent insulinotropic polypeptide (GIP) (also known as gastric inhibitory polypeptide) in K-cells. This incretrin upregulates insulin synthesis in the pancreatic beta-cells.
  • GIP glucose-dependent insulinotropic polypeptide
  • Progesterone in milk fat co-inductor of insulin resistance
  • Steroid hormones are known to cross the blood-milk barrier. This effect has been recurred to for the diagnosis of the pregnancy of cows by analyzing the progesterone content of their milk (Fritsche S, Steinhart H. Occurrence of hormonally active compounds in food : a review. Eur. Food Res. Technol. 1999; 209: 153-179). Since the steroid hormone progesterone is distributed in the lipid phase, the concentration of progesterone in dairy products depends on their fat content.
  • progesterone concentrations are found to be 1.4 ⁇ g/l in low-fat milk, 10 ⁇ g/l in whole milk, 44.2 mg/kg in Gouda, 41.8-72.7 ⁇ g/kg in cream and up to 300 ⁇ g/kg in butter (Fritsche S, Steinhart H. Occurrence of hormonally active compounds in food : a review. Eur. Food Res. Technol. 1999; 209: 153-179).
  • progesterone continues to be accumulated in the tissue in perpetually pregnant dairy cows of Western dairy farming and passes into the milk, an unphysiologically increased progesterone content of milk as compared to former times is to be assumed from the "industrialized technology of milk recuperation". This could be another unrecognized risk factor of Western life style.
  • the high progesterone content of these products allows for a possible daily progesterone intake of from 40 to 50 ⁇ g, which reaches the dose range of the progestogen fraction of an ethical oral contraceptive.
  • the extremely resistant progesterone of the lipid phase of dairy products adds to the load from steroid hormones.
  • the daily uptake of bovine progesterone must be seen in an overall consideration with the uptake of progestogen-containing oral contraceptives, since the progestogenic effects of nutritive and iatrogenic progestogens are additive.
  • PCOS patients represent a special risk group, being disposed to developing diabetes mellitus, cardiovascular diseases and cancer (F ⁇ rstenberger G, Senn H-J. Insulin-like growth factors and cancer. Lancet 2002; 3: 298-302; Druckmann R, Rohr UD. IGF-I in gynaecology and obstetrics: update 2002. Maturitas 2002; 41 (Suppl 1) : S65-S83). Not only increased insulin and IGF-I serum levels are to be expected therefrom, but also a progesterone-induced increase of the autocrine production of GH in peripheral tissues.
  • progesterone increases the peripheral concentration of GH , which stimulates the local and systemic IGF-I secretion (Cagnacci A, Ferrari S, Tirelli A, Zanin R, Volpe A. Insulin sensitivity and lipid metabolism with oral contraceptives containing chlormadinone acetate or desogestrel : a randomized trial. Contraception 2009; 79: 111-116).
  • This observation illustrates that a molecular cross-talk between the GH/IGF-1 axis and steroid hormones, such as progesterone, exists in mammals (Cagnacci A, Ferrari S, Tirelli A, Zanin R, Volpe A. Insulin sensitivity and lipid metabolism with oral contraceptives containing chlormadinone acetate or desogestrel : a randomized trial. Contraception 2009; 79: 111-116).
  • Lactogens placental lactogen and/or prolactin induce this up-regulation and remain elevated throughout gestation [116b]. There is no doubt that prolactin is a most important inducer of postnatal beta-cell proliferation (postnatal beta- cell burst) and insulin secretion.
  • colostrum of various species including human and bovine colostrum (500-800 ng/ml) contains very high amounts of prolactin.
  • Cow milk contains high levels of bovine prolactin (6-8 ng/ml) [3].
  • Human prolactin compared to bovine prolactin exhibits 73.1% protein identity and 80.3% DNA identity.
  • Prolactin is known to be absorbed in the intestine during the postnatal period.
  • continuous cow milk consumption in infancy and adulthood may result in increased intestinal prolactin absorption, especially in conditions with disturbed intestinal permeability barrier.
  • Alpha-lactalbumin is a unique protein of milk which contains high amounts of tryptophane, the precursor of serotonin (5- hydroxytryptamine) which stimulates the secretion of pituitary GH and prolactin (Markus CR. Dietary amino acids and brain serotonin function; implications for stress-related affective changes. Neuromol Med 2008; 10: 247).
  • milk and especially whey proteins containing alpha-lactalbumin will increase postprandial prolactin and GH levels which exert adverse mitogenic effects on pancreatic beta-cells (promotion of type 2 diabetes mellitus), on adipocytes (promotion of obesity) and other somatic cells like cancer cells (promotion of cancer).
  • Cow milk and cow milk protein consumption with its high insulin and IGF-I stimulatory effects has to be regarded as a violation of a physiological principal in mammalian nutrition developed during the eons of mammalian evolution.
  • the short-sighted view on the beneficial effects of milk consumption on bone formation and bone mineralization ignores already well documented facts of harmful disease- and cancer promoting effects of milk protein consumption.
  • This scientific principle can be applied to insulin/IGF-1 signaling in various cell systems. According to the presented hypothesis cow milk consumption has to be regarded as a health hazard for humans which afford immediate intervention.
  • the object of the present invention to overcome the drawbacks of prior art, especially by reduction of the insulinotropic effects of milk.
  • the solution to the health hazards of milk is the modification/attenuation of milk ' s insulinotropic and mitogenic properties.
  • a measure of the insulinotropic effect of milk is the insulinemic index of milk.
  • the insulinemic index of milk ranges between 90-148 [Ostman EM, LiIj berg Elmstahl HGM et al. : Inconsistency between glycemic and insulinemic reponses to regular and fermented milk products. Am J Clin Nutr 2001; 74:96- 100; Hoyt G, Hickey MS, Cordain L. Dissociation of the glycaemic and insulinaemic responses to whole and skimmed milk. Br J Nutr 2005; 93: 175- 177; Holt S, Brand Miller J, Petocz P. An insulin index of foods: the insulin demand generated by 1000-kJ portions of common foods.
  • Major contributors to milk ' s high insulinemic index are the GIP secretion induced by whey proteins, especially alpha-lactalbumin, the growth factors of the whey protein fraction, especially bovine prolactin and betacellulin and the IGF-I which is transported in the casein fraction of milk.
  • the method of the invention comprises the reduction of the content or activity of at least one of alpha-lactalbumin, ghrelin, betacellulin or prolactin.
  • the major focus of the invention is the reduction of alpha- lactalbumin as a most important precursor for pituitary GH and prolactin secretion as well as intestinal incretin formation (GIP, GLP-I and cholecystokinin)
  • the method of the invention is also a method of treating milk to reduce the ability of milk to induce GH and prolactin in a human being upon consumption.
  • a further embodiment is a method of treating casein to reduce the ability of casein to induce IGF-I in a human being upon consumption together with treating whey proteins to reduce the ability of whey proteins to induce insulin in a human being upon consumption.
  • milk is adjusted to have an insulinemic index between 40 and 80.
  • the insulinemic index is defined according to Holt S, Brand Miller J, Petocz P.
  • An insulin index of foods the insulin demand generated by 1000-kJ portions of common foods. Am J Clin Nutr 1997; 66: 1264-1276]
  • the insulinemic index is in the range of 40 to 50.
  • the process comprises the step of a hydrolytic treatment.
  • the hydrolytic treatment is conducted until the ability of casein to induce IGF-I and/or the ability of whey proteins to induce insulin and/or the ability of milk to induce growth hormone and/or the content or activity of ghrelin or betacellulin or alpha-lactalbumin is reduced.
  • the hydrolytic treatment can be conducted using one or more proteases, preferably from microorganisms, bacteria or fungi.
  • One very preferred treatment is directed against content or activity of ghrelin and/or betacellulin.
  • the treatment either comprises a hydrolytic treatment to hydrolyze the peptide structure of ghrelin and/or betacellulin.
  • a further possibility to reduce the activity of bovine ghrelin would be the addition of an anti-ghrelin Spiegelmer (Kobelt P et al. Anti-ghrelin Spiegelmer NOX-BI l inhibits neurostimulatory and orexigenic effects of peripheral ghrelin in rats. Gut 2006; 55:788-792; Shearman LP et al. Ghrelin neutralization by a ribonucleic acid-SPM ameliorates obesity in diet-induced obese mice. Endocrinology 2006; 147: 1517-1526). This would also work with betacellulin Spiegelmer.
  • a further possibility is the specific inactivation of ghrelin by hydrolyses of the acyl group on Ser-3.
  • a further possibility is the removal of ghrelin and/or betacellulin by absorption, especially immunoabsorption.
  • Filtration can for example be used to separate soluble whey proteins from casein proteins which have a higher molecular weight.
  • Absorptive material may be used to bind materials from the milk, especially when used in form of an affinity treatment.
  • affinity adsorption is suitable.
  • galactose or galactosyltransferase are useful. They could be coated on beads, surfaces or the like.
  • alpha-lactalbumin is denatured by high-pressure treatment as described in Huppertz T, Fox PF, de Kruif KG, Kelly AL. High- pressure induce changes in bovine milk proteins: a review. Biochim Biophys Acta 2006; 1764: 593-598.
  • a method to increase the content of alpha-lactalbumin is described in Kiesner C et al. (2000) Manufacturing of ⁇ -lactalbumin-enriched whey systems by selective thermal treatment in combination with membrane processes. Lait 80: 99-111. In a modified way, this method can also be used to reduce the content of alpha-lactalbumin.
  • prolactin affinity binding procedures For the removal of prolactin affinity binding procedures are applied. Biotechnologically produced prolactin binding proteins are fixed to adsorber systems or beads to remove free prolactin and bovine lactogen of milk.
  • a further embodiment of the invention additionally comprises a step to reduce bovine IGF-I in milk.
  • a person skilled in the art is able to modify the milk to adjust the respective levels of insulinotropic factors in a way that milk or milk- derived products, especially the alpha-lactalbumin amount of the whey protein fraction for the production of infant formula will exhibit an insulinemic index in the comparable range of the insulinemic index of human breast milk.
  • the produced future whey fraction will be adjusted in a way that infant formula feeding to a human newborn will exert postprandial insulin, glucose-dependent insulinotropic polypeptide and IGF-I responses comparable to the postprandial and long-term responses of physiologic breast-feeding.
  • a further embodiment of the invention is milk or a product from milk wherein the milk has been treated according to the process of the invention.
  • a further embodiment is a milk or a product from milk, wherein
  • casein is modified to reduce the ability of casein to induce IGF-I in a human being upon consumption
  • - whey proteins are modified to reduce the ability of whey proteins to induce insulin in a human being upon consumption or
  • - milk is modified to reduce the ability of milk to induce growth hormone in a human being upon consumption or - milk is modified to reduce the content or activity of alpha-lactalbumin
  • - milk is modified to reduce the content or activity of ghrelin or
  • - milk is modified to reduce the content or activity of prolactin.
  • the whey protein fraction is preferentially modified especially alpha-lactalbumin.
  • casein to reduce the ability of casein to induce IGF-I in a human being upon consumption of the milk and/or
  • the whole growth hormone containing basic whey fraction (with IGF-I, IGF-I, PDGF, FGF, TGFbeta, betacellulin, prolactin and alpha-lactalbumin) is removed from pasteurized raw milk.
  • IGF-I, IGF-I, PDGF, FGF, TGFbeta, betacellulin, prolactin and alpha-lactalbumin is removed from pasteurized raw milk.
  • One possible method follows the technique of LACTERMIN production by ultrafiltration and column chromatography described in Dyer et al. Food and Chemical Toxicology 46 (2008), 1659-1665. The combination of ion exchange chromatography and micro- and ultrafiltration of milk is appropriate.
  • the use of the treated milk of the invention is especially useful for the preparation of milk products, especially in the field of baby food and infant formula.
  • the milk of the invention is further useful for the preparation of a product for the treatment or prevention of disease selected from diabetes type II and obesity.
  • the milk of the invention with reduced insulinemic index is useful for adolescents to prevent and treat acne and other hyperproliferative diseases like psoriasis.
  • Figure 1 shows IGF-I, IGF-2 and insulin signal transduction and receptor cross-reactivity
  • Figure 2 shows insulinotropic and IGF-I inducing effect of milk protein and milk protein fractions
  • Figure 3 shows synopsis of milk and milk protein induced disturbances of insulin/IGF-1 signaling from fetal life to senescence and associated chronic diseases of Westernized societies.
  • ACTH adrenocorticotropic hormone
  • AGA appropriate for gestational age
  • IGF insulin-like growth factor
  • IGFBP IGF binding protein
  • IGFlR IGF-I receptor
  • IGF2R IGF- 2 receptor
  • MAPK mitogen activated protein kinase
  • PCOS polycystic ovary syndrome
  • PI3K phosphoinositide-3-kinase
  • SREBP sterol response element binding protein

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Abstract

La présente invention a pour objet un procédé permettant de traiter du lait, des produits lactés ou une formulation pour bébés à base de lait pour obtenir du lait, comprenant au moins l'une des étapes consistant : a) à traiter le lait pour réduire la teneur ou l'activité de l'alpha-lactalbumine ou; b) à traiter la caséine pour réduire la capacité de la caséine à induire l'IGF-1 chez un être humain qui en consomme et à traiter les protéines de lactosérum pour réduire la capacité des protéines de lactosérum à induire l'insuline chez un être humain qui en consomme; c) à traiter le lait pour réduire la capacité du lait à induire l'hormone de croissance chez un être humain qui en consomme; d) à traiter le lait pour réduire la teneur ou l'activité de la prolactine; e) à traiter le lait pour réduire la teneur ou l'activité de la bêtacelluline; f) à traiter le lait pour réduire la teneur ou l'activité de la ghréline, un indice insulinémique du lait étant de préférence modifié de sorte à être compris dans la gamme allant de 40 à 80. Les produits lactés sont moins insulinotropes, moins mitogènes en comparaison avec le lait et les produits lactés non traités.
PCT/EP2010/054937 2009-04-15 2010-04-15 Lait et produits lactés modifiés pour présenter un indice insulinémique réduit et/ou une activité mitogène réduite WO2010119088A2 (fr)

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