Fetal Insulin-Like Growth Factor-2 Production Is Impaired in the GK Rat Model of Type 2 Diabetes

Abstract

At late fetal age (21.5 days postcoitum [dpc]), GK rats present a severely reduced ␤-cell mass compared with Wistar rats. This anomaly largely antedates the onset of hyperglycemia in GK rats. Thus, the ␤-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 ␤-cell mitogenic response to IGFs in vitro is kept intact, therefore suggesting that the direct biological action of IGFs on fetal GK ␤-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 ␤-cell growth in the fetal GK rat.

Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto–Kakizaki rat model of type 2 diabetes

“…Our present findings are consistent with the maintenance of IGF2 responsiveness in GK beta cells and their cell precursors in pancreatic rudiments. Moreover, these data are in agreement with previous results demonstrating that IGF1 and IGF2 stimulated beta cell replication in fetal GK isolated islets [5]. Some factors such as hepatocyte growth factor and glucagon-like peptide 1 are known to influence the differentiation of progenitors into endocrine cells [13].…”

“…We have previously shown that hepatic and pancreatic Igf2 mRNA were reduced at the end of fetal GK life [5].…”

A euglycaemic/non-diabetic perinatal environment does not alleviate early beta cell maldevelopment and type 2 diabetes risk in the GK/Par rat model

“…1 and Table 1). These data confirm and extend our earlier reports of decreased transcript levels of Pdx1, Neurog3 (also known as Ngn3) and Igf2 [16,18] and reduction in pancreatic IGF2 and IGF1R protein levels [16] in E18.5 GK stock fetuses.…”

Impact and Mechanisms of Pancreatic Beta-Cell Mass Programming by Maternal Diabetes - Insight from Animal Model Studies

“…Defective signalling through the IGF2/IGF1-R pathway may represents the primary instrumental anomaly since IGF2 and IGF1-R protein expressions are already decreased within the GK/Par pancreatic rudiment at E13, at a time when beta-cell mass (first wave of beta cell expansion) is in fact normal (Miralles & Portha, 2001). Low levels of pancreatic IGF2, associated with beta-cell mass deficiency, are maintained thereafter within the fetal pancreas (Serradas et al, 2002). Crossbreeding protocols between non-diabetic W and diabetic GK rats showed that in late gestation (E18), pancreatic IGF2 protein expression was as low in GKmother/GKfather and Wmother/GKfather crosses than in GKmother/GK father crosses (Serradas et al, 2002).…”