No abstract

The importance of the intrauterine and neonatal metabolic environment as possible teratogenic determinants of predispositions to diabetes, obesity and cardiovascular diseases is discussed. Epidemiological, clinical and experimental results suggest that gestational diabetes or even slightly impaired glucose tolerance during pregnancy are important risk factors for the development of an increased Type II- and even Type I diabetes susceptibility in the offspring. In addition, early prenatal undernutrition might also predispose to enhanced risk of Type II diabetes, whereas perinatal overnutrition seems to enhance predominantly Type I diabetes susceptibility. In this context, fetal and/or neonatal hyperinsulinism occurring during a critical period of brain development and leading to permanent malorganization of hypothalamic regulation centres for metabolism and hence to malprogramming of the hypothalamo-pancreatic system, is discussed as a possible reason for lifelong enhanced diabetes susceptibility. In view of epidemiological and experimental findings, an epigenetic maternofetal transmission of such acquired persistent modifications can run over several generations, mediated by gestational hyperglycaemia and fetal or neonatal hyperinsulinism. In conclusion, a partial prophylaxis of diabetes mellitus, obesity and cardiovascular diseases appears to be possible by prevention of gestational diabetes--even mild forms of impaired glucose tolerance during pregnancy--as well as early prenatal undernutrition and perinatal overnutrition.

Early postnatal overnutrition is a risk factor for obesity in juvenile and adult life. Underlying pathophysiological mechanisms are still unclear. Hypothalamic neuropeptides are decisively involved in the regulation of body weight and food intake. In this study, we investigated consequences of early postnatal overnutrition, as compared to normo-and undernutrition, on NPY within the arcuate nucleus and paraventricular nucleus (PVN). The normal litter size of Wistar rats was adjusted on the third day of life from 10 pups (normal litters, NL; normonutrition) to only three newborns (small litters, SL; overnutrition) or 18 pups per mother (large litters, LL; undernutrition). SL rats developed clear overweight until the day 21 of life (P<0.0001), as well as hyperleptinaemia (P<0.001), and hyperinsulinaemia (P<0.01). LL rats were underweight and had decreased leptin and insulin concentrations. Using radioimmunoassay, NPY contents were determined in hypothalamic micropunches, and immunocytochemistry for NPY was performed in serial hypothalamic sections on day 21 of life. While in the underweight, hypoleptinaemic, and hypoinsulinaemic LL rats increased concentrations of NPY in the arcuate nucleus and PVN were observed, no decrease in NPY content was found in the overweight, hyperleptinaemic, and hyperinsulinaemic SL rats. Moreover, the percentage of NPY-immunopositive neurones per total number of neurones was increased not only in the LL rats, but also in the SL rats. Since the NPY system is functionally mature already at this age, these findings might indicate an acquired resistance of the hypothalamic NPY system to increased levels of insulin and/or leptin in early postnatally overfed SL rats.