In vitro studies on purified rat beta cells have indicated a functional diversity among insulin-containing cells. Intercellular differences were found in the rates of glucose-induced insulin synthesis and release. They are attributed to differences in cellular thresholds for glucose utilization and oxidation, as can be caused by varying activities in rate limiting steps such as glucokinase-dependent phosphorylation. The percent of functionally active beta cells increases dose-dependently with the glucose concentration, making cellular heterogeneity and its regulation by glucose major determinants for the dose-response curves of the total beta-cell population. Beta cells which are already responsive to low glucose concentrations are characterized by a higher content in pale immature granules; their activated biosynthetic and secretory activity accounts for preferential release of newly-formed hormone by the total beta-cell population. At any glucose level, the amplitude of insulin release depends on the percent glucose-activated cells and their cyclic AMP content, an integrator of (neuro)hormonal influences. The in vitro described heterogeneity in beta-cell functions may bear physiological relevance as several of its characteristics are also detectable in intact pancreatic tissue; furthermore, in vitro signs of heterogeneity can be altered by prior in vivo treatment indicating that they express properties of the cells in their in situ configuration. Elevated basal levels of (pro)insulin may reflect the existence of an increased number of beta cells that are activated at low physiologic glucose concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

A prospective follow-up study of 877 children born after ICSI was carried out. The aim of this study was to compile data on karyotypes, congenital malformations, growth parameters and developmental milestones so as to evaluate the safety of this new technique. The follow-up study included agreement to genetic counselling and prenatal diagnosis and was based on a physical examination at the Centre for Medical Genetics (Dutch-speaking Brussels Free University, Brussels, Belgium) at 2 months, 1 year and 2 years, when major and minor malformations and a psychomotor evolution were recorded. Between April 1991 and July 1995, 904 pregnancies obtained after intracytoplasmic sperm injection (ICSI) led to the birth of 877 children (465 singletons, 379 twins and 33 triplets). Prenatal diagnosis determined a total of 486 karyotypes, of which six were abnormal (1.2%) and six (1.2%) were familial structural aberrations, all transmitted from the father. This slight increase in de-novo chromosomal aberrations and the higher frequency of transmitted chromosomal aberrations are probably linked directly to the characteristics of the infertile men treated rather than to the ICSI procedure itself. In all, 23 (2.6%) major malformations were observed in the children born, defined as those causing functional impairment or requiring surgical correction. No particular malformation was disproportionately frequent. Compared with most registers of children born after assisted reproduction and with registers of malformation in the general population, the figure of 2.6% was within the expected range. These observations should be further completed by others and by collaborative efforts. In the meantime, patiens should be counselled about the available data before any treatment: the risk of transmitted chromosomal aberrations, the risk of de-novo, mainly sex chromosomal, aberrations and the risk of transmitting fertility problems to the offspring. Patients should also be reassured that there seems to be no higher incidence of congenital malformations in children born after ICSI.

The aim of this prospective follow-up study of children born after intracytoplasmic sperm injection (ICSI) was to compile data on karyotypes, congenital malformations, growth parameters and developmental milestones in order to evaluate the safety of this new technique. The study design included karyotyping of the parents and their agreement to genetic counselling and prenatal diagnosis and it was based on a physical examination of the child at the Centre for Medical Genetics at the ages of 2 months, 1 year and at 2 years, where major and minor malformations and psychomotor evolution are recorded. Here we describe the first 57 children born from 40 ICSI pregnancies with epididymal spermatozoa (group 1), the first 50 children born from 34 ICSI pregnancies with testicular spermatozoa (group 2) and the first 58 children born from 48 pregnancies after replacement of cryopreserved ICSI embryos (group 3). Parental karyotypes were obtained from only 72/246 (29%) parents and were all normal. Prenatal karyotypes were determined for a total of 70 samples (40%): 21 in group 1, 15 in group 2 and 34 in group 3. In this last group 2 abnormal 47,XXY karyotypes (5.8%) and no structural aberrations were found. This increase in de-novo sex-chromosomal aberrations has already been described with regard to the first 877 children born after ICSI carried out at our Centre and is probably linked directly to the characteristics of the infertile men treated rather than to the ICSI procedure itself. Major malformations, defined as those causing functional impairment or requiring surgical correction, were observed in four children: two born after ICSI with epididymal spermatozoa, one after ICSI with testicular spermatozoa and one after ICSI and cryopreservation. No particular malformation was disproportionally frequent. In the follow-up examinations at 2 months (107/161 or 66.5%) and at 1 year (37/161 or 22.9%), no additional anomalies were observed. Lost for follow-up rate at 2 months was 33.5%. These observations on a limited number of children do not suggest a higher incidence of diseases linked to imprinting, nor do they suggest a higher incidence of congenital malformations. These observations are still limited in number and should be further completed by others and by collaborative efforts. In the meanwhile patients should be told about the available data before any treatment: there appears to be some risk of transmitted chromosomal aberrations, of de-novo, mainly sex-chromosomal aberrations and of transmitting fertility problems to the offspring. Patients should also be reassured that until now there seems to be no higher incidence of congenital malformations in children born after ICSI with epididymal or testicular spermatozoa or after replacement of ICSI embryos.

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