ABSTRACT
<p><b>OBJECTIVE</b>To determine the molecular mechanisms linking intrauterine growth restriction (IUGR) to adult type 2 diabetes mellitus, the effect of IUGR on the hepatic post-receptor insulin-signaling pathway was investigated in the adult offspring.</p><p><b>METHODS</b>The IUGR model was prepared by maternal protein-malnutrition. Western blotting analysis was undertaken to assess hepatic expression of insulin receptor substrate (IRS-2), phosphoinositol 3-kinase (PI-3K), protein kinase B (PKB), phosphorylated PKB-Ser473 and glycogen synthase kinase (GSK) 3 in 8-week-old male IUGR rats.</p><p><b>RESULTS</b>The basal levels of PI-3K protein decreased in IUGR rats compared with normal controls (p<0.01), whereas GSK-3beta protein level significantly increased in IUGR rats (p<0.01). Both PKB and phosphorylated PKB-Ser473 protein levels significantly decreased in the liver of IUGR rats compared with normal controls (p<0.01)). After insulin administration, phosphorylated PKB-Ser473 significantly increased to 182% of basal level in control rats(p<0.01); However, phosphorylation of PKB which responded to insulin was markedly blunted in IUGR rats compared with controls and only increased to 123% of basal level (p<0.05).</p><p><b>CONCLUSIONS</b>The level of PI-3K and PKB and phosphorylated PKB-Ser473 expression decreased in the liver of IUGR rats, whereas the levels of GSK-3beta protein increased. It may contribute to the pathogenesis of insulin resistance in the IUGR rats.</p>
Subject(s)
Animals , Female , Male , Rats , Fetal Growth Retardation , Metabolism , Glycogen Synthase Kinase 3 , Glycogen Synthase Kinase 3 beta , Insulin Receptor Substrate Proteins , Insulin Resistance , Liver , Metabolism , Phosphatidylinositol 3-Kinases , Physiology , Proto-Oncogene Proteins c-akt , Rats, Wistar , Signal Transduction , PhysiologyABSTRACT
<p><b>OBJECTIVE</b>To investigate the effects of intrauterine growth retardation (IUGR) caused by malnutrition during pregnancy on the acetylation of histone H3 and expression of histonedeacetylase1(HDAC1) in the hepar of the adult offspring and to explore the relationship between them.</p><p><b>METHODS</b>Male 8-week-old offspring from maternal protein-malnutrition dams were studied. The expression of HDAC1 mRNA in the hepar was measured by fluorescent quantization RT-PCR. The levels of hepatic nuclear HDAC1 protein and acetylation of histone H3/K9 were assessed by Western blot.</p><p><b>RESULTS</b>The hepatic HDAC1 mRNA expression in IUGR rats was reduced to 54% of that of normal control rats (t=2.042, p<0.05). A decline in nuclear expression of HDAC1 protein (438 +/- 47) was also noted when compared with normal controls (1,128 +/- 110) (t=2.179, p<0.05). In contrast, the percentage of acetylated histone H3/K9 in IUGR rats (17.3 +/- 1.6%) increased significantly compared with that of normal control rats (10.5 +/- 1.2%) (t=3.597, p<0.01). The level of acetylated histone H3/K9 was negatively correlated with the HDAC1 protein concentration (r=-0.781, p<0.01).</p><p><b>CONCLUSIONS</b>Increased hepatic acetylation of histone H3 in the IUGR offspring might be caused by decreased HDAC1 expression in nuclear protein. This may contribute to the transcription change of some genes in the hepar.</p>