We have recently shown that maternal food restriction during late pregnancy decreased beta-cell mass in the offspring at birth. Prolonged maternal malnutrition until weaning led to irreversible decrease of beta-cell mass in the adult male progeny. During pregnancy, the maternal endocrine pancreas demonstrates an acute and reversible increase in beta-cell mass. The aim of this work was to investigate whether perinatal malnutrition could have long-lasting effects on glucose homeostasis and the adaptation of the endocrine pancreas to a subsequent pregnancy. This study was conducted on 4- and 8-month-old female rats malnourished during their perinatal life and on age-matched control animals. Oral glucose tolerance tests (OGTT), pancreatic insulin content, and islet mass quantitation after dithizone staining were performed on the same animals. Four-month-old nonpregnant previously malnourished animals showed normal glucose tolerance but a significant decrease in insulin secretion during OGTT. These animals were, however, still able to adapt pancreatic insulin contents and doubled their islet mass in late gestation. At 8 months of age, insulin content before pregnancy was reduced to half that of controls. Moreover, it did not show the characteristic increase during gestation that could still be observed in pregnant control females. In those control animals, the islet mass increased regularly until late gestation (14.1+/-1.8 mg at day 20.5, vs. 9.8+/-1.2 mg, nonpregnant), whereas in previously malnourished animals the islet mass remained throughout pregnancy similar to the nonpregnant values (8.5+/-1.4 mg at day 20.5 vs. 8.9+/-3.6 mg, nonpregnant). In conclusion, early malnutrition has dramatic consequences on the capacity of the endocrine pancreas to meet the increased insulin demand during pregnancy and aging.