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      Temporal Changes in Insulin-Like Growth Factors I and II and in Insulin-Like Growth Factor Binding Proteins 1, 2, and 3 in Human Milk

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          Abstract

          Aim: To evaluate the postpartum time course of changes in insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Methods: Breast milk IGF-I and IGF-II and IGFBP-1, IGFBP-2, and IGFBP-3 levels were determined in 23 women with babies born at term, from day 4 until up to 9 months after birth. Results: The IGFBP-3 levels were highest from day 4 to day 6 and then decreased by days 10–12. In contrast, IGF-I and IGF-II and IGFBP-1 and IGFBP-2 showed little change over the first 2 weeks after birth. Subsequently, all the IGF components showed a moderate decline over approximately the first 1–3 months and then stable levels up to 9 months after birth. Conclusion: Although the possibility cannot be excluded that these changes in levels of IGFs and their binding proteins in human milk represent passive loss from the mammary gland, we speculate that higher early levels of the human milk IGF system contribute to maturation of the infant gut.

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          Most cited references 21

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          Colostral and milk insulin-like growth factors and related substances: mammary gland and neonatal (intestinal and systemic) targets.

          The identification of hormones and regulatory factors in colostrum and milk has led to intensive investigations on their roles in the development and maintenance of the mammary and neonatal tissues. Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in transgenic mice influence mammary biology gland towards the end of lactation. In the bovine, IGFBP-3 is the major IGFBP in mammary secretions. In addition to binding IGFs, IGFBP-3 also binds to lactoferrin (Lf). Secreted IGFBP-3 re-enters mammary epithelial cells and with the presence of a nuclear localization sequence, IGFBP-3 and Lf enter the nucleus. Nuclear IGFBP-3 affects apoptotic signaling through the retinoic-x-receptors, while Lf affects apoptotic events through unknown mechanisms. Such interactions likely influence mammary development and involution. Furthermore, ingested colostral bioactive factors can exert regulatory functions in neonates. Intestinal receptors for IGFs and insulin are modified by age and/or diet. Feeding IGF-I had no effect, but colostrum extracts had small intestinal effects (stimulation of proliferation and villus size), suggesting that several factors, rather than one single bioactive factor were responsible. Systemic changes of metabolic and endocrine profiles in neonates depend on composition, amounts, time and duration of feeding colostrum. Early postnatal colostrum intake is not only important for the provision and absorption of immunoglobulins. Thus, in neonatal calves the lack of colostrum intake during the first 24h after birth results in a low immunoglobulin G, beta-carotene and Vitamin A status that persists for weeks and plasma patterns of fatty acids, essential amino acids and the glutamine/glutamate ratios are affected. In calves oral administration of IGF-I had no and feeding of colostrum whey extracts had only minor effects on metabolic and endocrine traits. Thus, mammary secretions influence regulatory functions of mammary and neonatal tissues.
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            Role of human milk components in gastrointestinal development: Current knowledge and future NEEDS

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              Changes in the Growth-Promoting Activity of Human Milk during Lactation

              We measured the concentrations of protein, insulin, and epidermal growth factor (EGF) in human milk from mothers delivering at term. Samples were obtained from d 1 (colostrum) to d 42 after birth. Human colostrum contains very high concentrations of protein [83.7 +/- 7.4 g/l (SEM)], insulin (3.75 +/- 0.88 nM), and EGF (53.9 +/- 6.9 nM). Similar concentrations have been measured in prebirth milk. Insulin, EGF, and protein in milk decline rapidly during the first few days of lactation but remain constant thereafter. Although the concentrations of insulin and EGF in mature milk are only 10% of those in colostrum, they are considerably higher than in serum. We also showed that human milk has a growth-promoting activity in cultured cells, causing a stimulation of protein synthesis in L6 myoblasts and 3T3-L1 fibroblasts and an increase in DNA synthesis in L6 cells and T47D breast cancer cells. This mitogenic activity declines as lactation progresses, with a similar time-course to the fall in insulin and EGF; however, the cell lines used here are not responsive to either of these two growth factors in the range of concentrations found in milk. This indicates that human milk also contains high concentrations of additional, unidentified growth factors. The occurrence of high concentrations of growth factors in milk suggests that they may be important for the proliferation and differentiation of infant tissues.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2008
                May 2008
                06 February 2008
                : 69
                : 5
                : 307-311
                Affiliations
                aFertility Associates, Ascot Integrated Hospital, Auckland, and bDepartment of Physiology, University of Auckland, Auckland, New Zealand; cEli Lilly, Bad Homburg, and University Children’s Hospital, Giessen, Germany
                Article
                114863 Horm Res 2008;69:307–311
                10.1159/000114863
                18259111
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, References: 31, Pages: 5
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