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

¹ Peninsula Medical School, Exeter, U.K.
² Royal Devon and Exeter Hospital, Exeter, U.K.
³ Regional Endocrine Laboratory, University Hospital Birmingham NHS Trust, Birmingham, U.K.
⁴ Case Western Reserve University, Cleveland, Ohio

Address correspondence and reprint requests to Professor Andrew T. Hattersley, Diabetes Research, Peninsula Medical School, Barrack Road, Exeter, EX2 5DW, U.K. E-mail: andrew.hattersley{at}pms.ac.uk

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 = 0.042). This difference was also seen in 17 discordant sibling pairs (600 vs. 720 g, P = 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 = 0.61, P < 0.001). Cord insulin concentrations were directly related to placental weight (r = 0.28) and birth weight (r = 0.36) (P < 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.

Abbreviations: EFSOCH, Exeter Family Study of Childhood Health • GCK, glucokinase

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