The growth and development of the placenta is critical to fetal growth and development; however, little is known regarding the mechanisms controlling placental growth and development. Human placental membranes are known to possess receptors for insulin-like growth factors I and II (IGF-I and IGF-II) from early gestation, and increasing evidence supports a major role for IGF-I and/or IGF-II in fetal growth and development. Therefore, the IGFs may also play a significant role in regulating placental growth and development. We report here that an adult human liver IGF-II cDNA hybridizes to poly(A)+ RNAs of human placentas from different gestational ages. There are four placental poly(A)+ RNA species that hybridize to IGF-II cDNA, the major one of which is about 6000 bases. The sizes of the hybridized transcripts are the same for placentas of different gestational ages. Furthermore, the IGF-II sequences expressed in the human placenta were quantitated by dot blot hybridization. The second trimester placenta expresses more IGF-II mRNA sequences than placenta of first trimester and term. Interestingly, the term placentas from diabetic pregnancies also express more of these sequences than those from normal pregnancies. These results suggest that there are developmental changes in the expression of the IGF-II gene in the placenta and that IGF-II may promote placental growth by way of an autocrine and/or paracrine mechanism. Moreover, fetuses developing in diabetic pregnancies receive a large influx of glucose, which in turn may stimulate the expression of IGF-II sequences in placenta, resulting in higher utilization of glucose and overgrowth of placenta. This may explain the macrosomia and high incidence of malformations and stillbirths known to result from pregnancies in diabetics.