Fetal Insulin-Like Growth Factor-2 Production Is Impaired in the GK Rat Model of Type 2 Diabetes
- Patricia Serradas1,
- Luis Goya2,
- Matthieu Lacorne1,
- Marie-Noëlle Gangnerau1,
- Sonia Ramos2,
- Carmen Alvarez2,
- Ana-Maria Pascual-Leone2 and
- Bernard Portha1
- 1Laboratory of Physiopathology of Nutrition, Université Paris, Paris, France
- 2Instituto de Bioquimica, Facultad de Farmacia, Ciudad Universitaria, Madrid, Spain
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.
Address correspondence and reprint requests to Dr. P. Serradas, Laboratory of Physiopathology of Nutrition, CNRS UMR 7059, Université Paris 7/Denis Diderot, 2 Place Jussieu, 75251 Paris Cedex 05, France. E-mail:.
Received for publication 19 April 2001 and accepted in revised form 8 November 2001.
BrdU, 5′-bromo-2′-deoxyuridine; dpc, days postcoitum; GH, growth hormone; IGFBP, IGF binding protein; PVDF, polyvinylidene fluoride; TBS, Tris-buffered saline.