The Mechanisms Of Abnormal Glucosemetabolism And Chronic Hepatic Injury Induced By Intrauterine Hyperglycemia In Offspring

Part ? Establishment of gestational diabetes mellitus mouse model and examination of the expression of genes related to metabolism in liverObjectives:To establish the mouse model of gestational diabetes mellitus(GDM)and to investigate the glucose metabolism of GDM offspring mice and genes related to metabolism in liver.Methods:Pregnant female mice were injected with streptozotocin(STZ)to induce GDM.The glucose tolerance and insulin tolerance levels of male offspring at age of 8 weeks and 20 weeks in control and GDM groups were examined by the glucose tolerance test(GTT)and insulin tolerance test(ITT),respectively.The mRNA expression of the genes related to metabolism in liver was detected by real-time PCR(qPCR).Results:Compared to the control group,the male and female offspring in the F1-GDM group had significantly increased serum blood glucose levels in GTT and ITT,suggesting slight insulin resistance in offspring of mothers with GDM.On the other hand,we found that the genes related to glycogen synthesis and fat synthesis in F1-GDM liver were down-regulated.Conclusions:Intrauterine hyperglycemia may result in the impaired glucose tolerance and downregulated expression of glycogen synthase gene and fat synthase gene in offspring.Part ? The altered expression levels of the hepatic immune receptors and chronic injury of liver in GDM offspring miceObjectives:To investigate the expression of hepatic immune receptors and the chronic hepatic injury in F1-GDM mice.Methods:Histochemical analysis(HE staining)was used to examine the liver of fetal male mice,adult mice at age of 8 and 20 weeks in F1-GDM group,respectively.Total RNA was extracted from liver samples by TRIzol Reagent.The expression of IL-1? IL-6r,CD36 and CD248 mRNAs were examined by qPCR.Western blot and immunohistochemistry analyses were used to examine the expression and intracellular location of IL-6r and CD248 proteins,respectively.Additionally,the expression of immune factors in Hepal-6 cells was detected by qPCR after exposed to a hyperglycemic medium.Results:Significantly higher levels of the IL-1?,IL-6r and CD248 were found in GDM fetal and adult offspring as compared to the normal controls.Immunohistochemical analysis and Western blot results showed that the protein expression levels of cell surface markers IL-6r and CD36 were significantly up-regulated.Moreover,we found that the IL-6r were also upregulated in Hepal-6 cells treated with high concentration of glucose in culture medium.Conclusions:Intrauterine hyperglycemia during pregnancy might directly lead to significantly up-regulated expression of immune-related cytokines in the liver of the offspring,suggesting that this is possibly causation of the chronic liver injury or inflammation in adult and aged mice.