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

Poor pregnancy outcome after octreotide treatment during pregnancy for familial hyperinsulinemic hypoglycemia: a case report

“…In contrast, a fetus without the mutation will have an appropriate insulin response that facilitates growth leading to an appropriate birth weight. This is in accordance with the studies from the group of Hattersley et al looking into the effect of fetal glucokinase mutations in offspring of women with Maturity Onset Diabetes of the Young 2 [ 8 ].…”

Poor pregnancy outcome after octreotide treatment during pregnancy for familial hyperinsulinemic hypoglycemia: a case report

“…In contrast, a fetus without the mutation will have an appropriate insulin response that facilitates growth leading to an appropriate birth weight. This is in accordance with the studies from the group of Hattersley et al looking into the effect of fetal glucokinase mutations in offspring of women with Maturity Onset Diabetes of the Young 2 [ 8 ].…”

Pancreas agenesis and fetal growth: a semiquantitative analysis

“…There were few placenta weights available for analysis; however, the findings would be consistent with a role of fetal insulin in determining final placenta size. This notion is supported by recent genetic data ( 52 , 53 ) and animal experiments ( 54 ).…”

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)…”

Poor pregnancy outcome after octreotide treatment during pregnancy for familial hyperinsulinemic hypoglycemia: a case report

“…In contrast, a fetus without the mutation will have an appropriate insulin response that facilitates growth leading to an appropriate birth weight. This is in accordance with the studies from the group of Hattersley et al looking into the effect of fetal glucokinase mutations in offspring of women with Maturity Onset Diabetes of the Young 2 [ 8 ].…”

Pancreas agenesis and fetal growth: a semiquantitative analysis

“…There were few placenta weights available for analysis; however, the findings would be consistent with a role of fetal insulin in determining final placenta size. This notion is supported by recent genetic data ( 52 , 53 ) and animal experiments ( 54 ).…”

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)…”

Poor pregnancy outcome after octreotide treatment during pregnancy for familial hyperinsulinemic hypoglycemia: a case report

“…In contrast, a fetus without the mutation will have an appropriate insulin response that facilitates growth leading to an appropriate birth weight. This is in accordance with the studies from the group of Hattersley et al looking into the effect of fetal glucokinase mutations in offspring of women with Maturity Onset Diabetes of the Young 2 [ 8 ].…”

Pancreas agenesis and fetal growth: a semiquantitative analysis

“…There were few placenta weights available for analysis; however, the findings would be consistent with a role of fetal insulin in determining final placenta size. This notion is supported by recent genetic data ( 52 , 53 ) and animal experiments ( 54 ).…”

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)…”