Regulation glycogen synthesis by newly discovered proteins in human placental microvascular endothelial cells under normo- and hyperglycaemic conditions

Diabetes during pregnancy has adverse effects on maternal and fetal metabolism, causing serious and occasionally life-threatening complications. One of the paradoxical changes in the diabetic placenta, that is involved in or might even cause the adverse outcome of diabetic pregnancies, is glycogen accumulation, occuring in marked contrast to glycogen loss in other organs. Recently, the general concept on glycogen metabolism had to be changed considerably by newly discovered proteins having the potential to be the key regulators of cellular glycogen synthesis: the autocatalytic glycogenin as primer, a new transglucosylase activity (proglycogen synthase) and the stable glycogen-precursor proglycogen. The proposed project aims to study the effect of hyperglycaemia on the balance between glycogenin, proglycogen and glycogen in human term placental microvascular endothelial cells, in order to test the hypothesis that accumulation of glycogen in the diabetic placenta is directly related to maternal glucose excess and is mediated by the recently discovered potential regulators of glycogen synthesis.

Diabetic pregnancies are a numerically major contributor to problems of pregnancy, which include fetal and newborn malformation, excessive growth at birth with difficult delivery and neonatal disease. These possible sequels underscore the high risk nature of diabetic pregnancies, that represent 5-10% of the total pregnancies in industrialised countries. The human placenta is a complex and so far poorly understood organ which plays the central metabolic role in pregnancy. It is clearly involved in or might even cause the adverse outcome of diabetic pregnancies. The levels of glycogenin, the newly discovered protein primer for glycogen synthesis, are elevated in placentae from gestational diabetic women. However, hyperglycaemia and hyperinsulinaemia promote glycogen deposition in cultured endothelial cells of the human term placenta independent of alterations in glycogenin levels with a much stronger effect of glucose. On the basis of these data we have developed the following hypothesis to explain the paradoxical accumulation of glycogen in the placenta of diabetic gravidas: Maternal glucose that is destined for transfer to the fetus crosses the placenta. Once within the fetal circulation, glucose is used to cover acute fetal metabolic and energy demands. The proportion of glucose that is not metabolized is then stored in various fetal tissues, predominantly liver, heart and skeletal muscle. When further glucose overload cannot be channeled into glycogen, because of a limited availability of glycogenin or other molecules needed for glycogen biosynthesis, these storage sites in the fetus proper are saturated. In this instance the excess fetal glucose will then be taken up by endothelial cells surrounding the placental vessels via specific carriers and converted into glycogen. This process may even be stimulated by the hyperglycaemia-associated fetal hyperinsulinaemia. The majority of insulin receptors at term of gestation is located on the cells of the endothelium and our in vitro data indicate a stimulatory effect of hyperinsulinaemia on glycogen in endothelial cells of the placenta. Others have found that insulin injections into the fetal circulation in rat leads to a doubling of placental glycogen levels whereas liver glycogen is only increased by 40%. This demonstrates the preferential routing of glucose for storage to the placenta under conditions of fetal hyperinsulinaemia as it is associated with modest increases in fetal and maternal glucose levels.