Mutations in the Glucokinase Gene of the Fetus Result in Reduced Placental Weight

Abstract

OBJECTIVE -In human pregnancy, placental weight is strongly associated with birth weight. It is uncertain whether there is regulation of the placenta by the fetus or vice versa. We aimed to test the hypothesis that placental growth is mediated, either directly or indirectly, by fetal insulin.RESEARCH DESIGN AND METHODS -Birth weight and placental weight were measured in 43 offspring of 21 parents with mutations in the glucokinase (GCK) gene (25 had inherited the mutation and 18 had not), which results in reduced fetal insulin secretion. Birth weight, placental weight, umbilical cord insulin, and maternal glucose and insulin concentrations were measured in 573 nondiabetic, healthy, term pregnancies.RESULTS -GCK mutation carriers were lighter and also had smaller placentas (610 vs. 720 g, P ϭ 0.042). This difference was also seen in 17 discordant sibling pairs (600 vs. 720 g, P ϭ 0.003). GCK mRNA was not detected in the placenta by RT-PCR. In the normal pregnancies, placental weight was strongly correlated with birth weight (r ϭ 0.61, P Ͻ 0.001). Cord insulin concentrations were directly related to placental weight (r ϭ 0.28) and birth weight (r ϭ 0.36) (P Ͻ 0.001 for both).CONCLUSIONS -These results suggest that insulin, directly or indirectly, plays a role in placental growth, especially as a mutation in the GCK gene, which is known to only alter fetal insulin secretion, results in altered placental weight. This finding is consistent with the preferential localization of the insulin receptors in the fetal endothelium of the placenta in the last trimester of pregnancy. Diabetes Care 31:753-757, 2008

The clinical management of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young

“…A C C E P T E D ACCEPTED MANUSCRIPT 16 (26). There was no difference in placental weight in both the GCK N/N and GCK N/M groups between those treated with insulin and those not treated with insulin (680 g vs 680g, respectively, p=0.69)…”

The Feto-placental Dialogue and Diabesity

“…It can stimulate (1) placental growth and also growth of the fetal heart, at least in non-human primates [29,30], (2) glycogen deposition in the placental endothelium (Desoye, Hiden unpublished) and (3) aerobic fetal metabolism. The latter will raise the demand for oxygen in the fetus.…”

Genetics in Gestational Diabetes Mellitus: Association with Incidence, Severity, Pregnancy Outcome and Response to Treatment

“…Velho et al has been arisen the importance of the mutation inheritance by the foetus [91] who demonstrated that a maternal mutation of MODY2 diabetes results in increased birth weight while a foetal mutation leads to reduced birth weight. Furthermore, Shields et al [92] reported reduced placental weight in mutation-carrying offspring as a result of reduced foetal insulin secretion while Spyer et al [93] showed increased foetal weight without restoration of the weight to normal by maternal insulin treatment. Additionally, the HNF4A maternal polymorphism has been associated with increased birth weight and, in some cases, with transient neonatal hypoglycaemia due to foetal hyperinsulinaemia while a dual opposite role in the b-cell activity during different periods of life has been proposed for this mutation [94].…”