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At late fetal age (21.5 days postcoitum [dpc]), GK rats present a severely reduced β-cell mass compared with Wistar rats. This anomaly largely antedates the onset of hyperglycemia in GK rats. Thus, the β-cell mass deficit could represent the primary defect leading to type 2 diabetes in the adult. The aim of this work was to investigate, in GK fetuses at the end of fetal age (21.5 dpc), whether impaired availability of growth factors such as insulin, growth hormone, and IGFs and their IGF binding proteins (IGFBPs) could be instrumental in this anomaly. Although it confirms that GK fetuses are hypoinsulinemic despite enhanced plasma glucose level due to maternal hyperglycemia, the present study shows for the first time that IGF-2 expression in the liver and pancreas and IGF-2 serum levels are decreased in GK fetuses. Serum level as well as liver and pancreatic mRNA expression of IGFBP-2 were found to be normal in GK fetuses, whereas serum level and liver mRNA expression of IGFBP-1 were increased. Finally, we found that the maximal β-cell mitogenic response to IGFs in vitro is kept intact, therefore suggesting that the direct biological action of IGFs on fetal GK β-cells is not grossly impaired. In conclusion, in GK fetuses at 21.5 dpc, the defective IGF-2 production appears to be an early landmark in the pathological sequence leading to retardation of β-cell growth in the fetal GK rat., This work was supported by DGICYT (Direccion General de Investigacion, Ciencia, Tecnologia, Ministerio de Educacion, Ciencia, Spain; Grant PM 97-0017), by a grant from the Ministe`re de l’Education Nationale, de l’Enseignement Superieur et de la Recherche (no. 95-G-0103; program interministeriel “Aliment Demain”), and by the France/Spain program for Science (Cooperation Franco-Espagnole Center National de la Recherche Scientifique/Consejo Superior Investigaciones Cientificas; projects 5249 and 7963). S. Ramos was a recipient of a fellowship from Conserjeria de Educacion y Cultura from Comunidad Autonoma de Madrid.