| dc.description.abstract | Despite strict glycemic control of the pregnant woman with type 1 diabetes fetal overgrowth is still common. The first trimester is often characterized by sub-optimal glucose levels and elevated HbA1C in early pregnancy is a predictor of fetal overgrowth. Altered placental nutrient transport has been implicated in fetal growth abnormalities and is suggested to be one mechanism contributing to a diverging fetal growth rate. However, the factors regulating placental transporters are not well established, in particular during early pregnancy. We hypothesized that placental transport of glucose and amino acids in early and late pregnancy are distinct and that glucose transport is sensitive to regulation primarily during the first trimester and may therefore be permanently affected by metabolic disturbances in early pregnancy, resulting in altered fetal growth. Expression of GLUT isoforms 1, 3 and 4 were examined in first trimester and term human placenta. GLUT1 levels were abundant at term whereas GLUT3 and 4 were markedly lower at term compared with early pregnancy. Regulation of glucose transport was assessed by 1 h incubation of villous fragments in insulin, leptin, cortisol, GH, IGF-I or glucose and by the subsequent uptake of 3-O-(methyl-14C)-D-glucose. Hormonal regulation of amino acid transporter system A was studied in first trimester fragments measuring the Na+-dependent uptake of 14C-methylaminoisobutyric acid (MeAIB). Insulin stimulated glucose uptake 2-fold in early pregnancy (6-8 weeks) but not at term, while system A activity was down regulated by GH in first trimester fragments. The effect of hyperglycemia (8-14 mM) on fetal growth and placental transport function were studied in pregnant rats given glucose (2g/kg, i.p.) on different days of gestation: Group1: one injection on GD10, Group2: three injections on GD10, Group3: six injections on GD10 and 11 and Group4: three injections on GD19. Fetal weights were increased by three and six hyperglycemic events in early pregnancy, whereas placental weights were unaltered in all groups. Subsequent transport measurements of glucose and MeAIB were carried out in vivo close to term (GD21) and placental expression of GLUT1, 3, SNAT2 (system A), LAT1 and 2 (system L) were studied in groups 2 and 3. Term placental system A transport was down regulated by six glucose injections on GD10 and 11. System L protein levels were unaltered by early hyperglycemia, however LAT 2 mRNA was down regulated. We conclude that the pattern of GLUT isoform expression is markedly different in early and late pregnancy. GLUT 4 may play a role in placental uptake of glucose during the first trimester and insulin is one regulator of glucose transport during this period. Regulation of system A is different in first trimester and term placentas. Early pregnancy hyperglycemia in the rat programs placental transport functions for the remainder of pregnancy. There is a dose-response relationship between the number of hyperglycemic events in early pregnancy and placental function and fetal growth. Since late pregnancy hyperglycemia did not alter fetal weight at term, we suggest that glucose control in early pregnancy is an important determinant for placental function and fetal growth throughout gestation. | en |
