Fetal insulin-like growth factor-2 production is impaired in the GK rat model of type 2 diabetes.
At late fetal age (21.5 days postcoitum [dpc]), GK rats present a severely reduced beta-cell mass compared with Wistar rats. This anomaly largely antedates the onset of hyperglycemia in GK rats. Thus, the beta-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 beta-cell mitogenic response to IGFs in vitro is kept intact, therefore suggesting that the direct biological action of IGFs on fetal GK beta-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 beta-cell growth in the fetal GK rat.
Serradas
Patricia
P
Laboratory of Physiopathology of Nutrition, Université Paris, Paris, France. serradas@paris7.jussieu.fr
Goya
Luis
L
Lacorne
Matthieu
M
Gangnerau
Marie-Noëlle
MN
Ramos
Sonia
S
Alvarez
Carmen
C
Pascual-Leone
Ana-Maria
AM
Portha
Bernard
B
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000196:embryology*; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000378:metabolism; D005333:Fetus / Q000502:physiology; D005865:Gestational Age; D066298:In Vitro Techniques; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood / Q000235:genetics; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008938:Mitosis / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017208:Rats, Wistar
D018969:Insulin-Like Growth Factor Binding Proteins; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II