It is increasingly accepted that alterations of the intrauterine and early postnatal nutritional, metabolic and hormonal environment may predispose individuals to development of diseases in later life. Results from studies of the offspring of diabetic mothers strongly support this hypothesis. It has also been suggested that being light at birth leads to an increased risk of the metabolic syndrome (Syndrome X) in later life (the Barker hypothesis). The pathophysiological mechanisms that underlie this programming are unclear. However, hormones are important environment-dependent organizers of the developing neuroendocrine-immune network, which regulates all the fundamental processes of life. Hormones can act as ‘endogenous functional teratogens’ when present in non-physiological concentrations, induced by alterations in the intrauterine or neonatal environment during critical periods of perinatal life. Perinatal hyperinsulinism is pathognomic in offspring of diabetic mothers. Early hyperinsulinism also occurs as a result of early postnatal overfeeding. In rats, endogenous hyperinsulinism, as well as peripheral or intrahypothalamic insulin treatment during perinatal development, may lead to ‘malprogramming’ of the neuroendocrine systems regulating body weight, food intake and metabolism. This results in an increased disposition to become obese and to develop diabetes throughout life. Similar malprogramming may occur due to perinatal hypercortisolism and hyperleptinism. With regard to ‘small baby syndrome’ and the thrifty phenotype hypothesis, we propose that early postnatal overfeeding of underweight newborns may substantially contribute to their long-term risk of obesity and diabetes. In summary, a complex malprogramming of the central regulation of body weight and metabolism may provide a general aetiopathogenetic concept, explaining perinatally acquired disposition to later disease and, thereby, opening a wide field for primary prevention.

1.
Hales CN, Barker DJ: Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992;35:595–601.
2.
Freinkel N, Metzger BE: Pregnancy as a tissue culture experience: the critical implications of maternal metabolism for fetal development; in Pregnancy, Metabolism, Diabetes, and the Fetus. Ciba Foundation Symposium 63. Amsterdam, Excerpta Medica, 1979, pp 3–23.
3.
Aerts L, Van Assche FA: Is gestational diabetes an acquired condition? J Dev Physiol 1979;1:219–225.
4.
Dörner G: Perinatal hormone levels and brain organization. Anatomical Neuroendocrinology 1975;1:245–252.
5.
Dörner G: Problems and terminology of functional teratology. Acta Biol Med Ger 1975;34:1093–1095.
6.
Dörner G: Hormones and Brain Differentiation. Amsterdam-Oxford-New York, Elsevier, 1976.
7.
Meaney MJ, Diorio J, Francis D, Widdowson J, LaPlante P, Caldji C, Sharma S, Seckl JR, Plotsky PM: Early environmental regulation of forebrain glucocorticoid receptor gene expression: implications for adrenocortical responses to stress. Dev Neurosci 1996;18:49–72.
8.
Dörner G, Plagemann A: Perinatal hyperinsulinism as possible predisposing factor for diabetes mellitus, obesity and enhanced cardiovascular risk in later life. Horm Metab Res 1994;26:213–221.
9.
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG: Central nervous system control of food intake. Nature 2000;404:661–671.
10.
Pettitt DJ, Baird HR, Aleck KA, Bennett PH, Knowler WC: Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy. N Engl J Med 1983;308:242–245.
11.
Silverman BL, Metzger BE, Cho NH, Loeb CA: Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism. Diabetes Care 1995;18:611–617.
12.
Dabelea D, Hanson RL, Lindsay RS, Pettitt DJ, Imperatore G, Gabir MM, Roumain J, Bennett PH, Knowler WC: Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 2000;49:2208–2211.
13.
Weiss PA, Scholz HS, Haas J, Tamussino KF, Seissler J, Borkenstein MH: Long-term follow-up of infants of mothers with type 1 diabetes: evidence for hereditary and nonhereditary transmission of diabetes and precursors. Diabetes Care 2000;23:905–911.
14.
Plagemann A, Harder T, Kohlhoff R, Rohde W, Dörner G: Overweight and obesity in infants of mothers with long-term insulin-dependent diabetes or gestational diabetes. Int J Obes Relat Metab Disord 1997;21:451–456.
15.
Plagemann A, Harder T, Kohlhoff R, Rohde W, Dörner G: Glucose tolerance and insulin secretion in children of mothers with pregestational IDDM or gestational diabetes. Diabetologia 1997;40:1094–1100.
16.
Harder T, Kohlhoff R, Dörner G, Rohde W, Plagemann A: Perinatal ‘programming’ of insulin resistance in childhood: critical impact of neonatal insulin and low birth weight in a risk population. Diabet Med 2001;18:634–639.
17.
Plagemann A, Harder T, Melchior K, Rake A, Rohde W, Dörner G: Elevation of hypothalamic neuropeptide Y-neurons in adult offspring of diabetic mother rats. Neuroreport 1999;10:3211–3216.
18.
Ogata ES, Collins JW Jr, Finley S: Insulin injection in the fetal rat: accelerated intrauterine growth and altered fetal and neonatal glucose homeostasis. Metabolism 1988;37:649–655.
19.
Plagemann A, Heidrich I, Götz F, Rohde W, Dörner G: Lifelong enhanced diabetes susceptibility and obesity after temporary intrahypothalamic hyperinsulinism during brain organization. Exp Clin Endocrinol 1992;99:91–95.
20.
Plagemann A, Heidrich I, Rohde W, Götz F, Dörner G: Hyperinsulinism during differentiation of the hypothalamus is a diabetogenic and obesity risk factor in rats. Neuroendocrinol Lett 1992;14:373–378.
21.
Harder T, Plagemann A, Rohde W, Dörner G: Syndrome X-like alterations in adult female rats due to neonatal insulin treatment. Metabolism 1998;47:855–862.
22.
Susa JB, Boylan JM, Sehgal P, Schwartz R: Impaired insulin secretion after intravenous glucose in neonatal rhesus monkeys that had been chronically hyperinsulinemic in utero. Proc Soc Exp Biol Med 1992;199:327–331.
23.
Harder T, Aerts L, Franke K, Van Bree R, Van Assche FA, Plagemann A: Pancreatic islet transplantation in diabetic pregnant rats prevents acquired malformation of the ventromedial hypothalamic nucleus in their offspring. Neurosci Lett 2001;299:85–88.
24.
Ravelli GP, Stein ZA, Susser MW: Obesity in young men after famine exposure in utero and early infancy. N Engl J Med 1976;295:349–353.
25.
Plagemann A, Harder T, Rake A, Voits M, Fink H, Rohde W, Dörner G: Perinatal elevation of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome x-like alterations in adulthood of neonatally overfed rats. Brain Res 1999;836:146–155.
26.
Plagemann A, Harder T, Rake A, Waas T, Melchior K, Ziska T, Rohde W, Dörner G: Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats. J Neuroendocrinol 1999;11:541–546.
27.
Plagemann A: Fetale Programmierung und Funktionelle Teratologie: Ausgewählte Mechanismen und Konsequenzen; in Gortner L, Dudenhausen JW (eds): Vorgeburtliches Wachstum und gesundheitliches Schicksal: Störungen-Risiken-Konsequenzen. Frankfurt/Main, Med. Verl.-Ges. Umwelt & Medizin, 2001, pp 65–78.
28.
Stettler N, Zemel BS, Kumanyika S, Stallings VA: Infant weight gain and childhood overweight status in a multicenter, cohort study. Pediatrics 2002;109:194–199.
29.
Davidowa H, Plagemann A: Decreased inhibition by leptin of hypothalamic arcuate neurons in neonatally overfed young rats. Neuroreport 2000;11:2795–2798.
30.
Davidowa H, Plagemann A: Inhibition by insulin of hypothalamic VMN neurons in rats overweight due to postnatal overfeeding. Neuroreport 2001;12:3201–3204.
31.
Franke K, Harder T, Aerts L, Melchior K, Fahrenkrog S, Rodekamp E, Ziska T, Van Assche FA, Dudenhausen JW, Plagemann A: ‘Programming’ of orexigenic and anorexigenic hypothalamic neurons in offspring of treated and untreated diabetic mother rats. Brain Res 2005;1031:276–283.
32.
Bouret SG, Draper SJ, Simerly RB: Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004;304:108–110.
33.
Vickers MH, Gluckman PD, Coveny AH, Hofman PL, Cutfield WS, Gertler A, Breier BH, Harris M: Neonatal leptin treatment reverses developmental programming. Endocrinology 2005;146:4211–4216.
Copyright / Drug Dosage / Disclaimer
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.
You do not currently have access to this content.