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Exogenous Corticosteroids and in Utero Oxygenation Modulate Indices of Fetal Insulin Secretion

Department of Obstetrics and Gynecology (J.V., R.v.B.), and Laboratorium voor Experimentele Geneeskunde en Endocrinologie (E.v.H., W.C.), Katholieke Universiteit Leuven, 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Johan Verhaeghe, M.D., Department of Obstetrics and Gynecology, U.Z. Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. E-mail: johan.verhaeghe{at}uz.kuleuven.ac.be.

Low birth weight has long-term effects on glucose-insulin homeostasis. Factors that could mediate intra-uterine "programing" of glucose homeostasis include endogenous and exogenous glucocorticoids, adipose tissue-secreted factors such as adiponectin, and in utero hypoxia. Here, we studied 123 fetuses with gestational age (GA) between 25 and 37 wk and birth weight SD score (BW SDS) between –2.79 and 2.42. We measured proinsulin, C-peptide, insulin, and adiponectin in umbilical vein (UV) plasma and calculated the proinsulin to insulin ratio as a measure of ß-cell secretory function. These indices were related to GA, BW SDS, time since the last maternal betamethasone administration, and blood gas data.

Insulin and C-peptide were correlated with BW SDS but not GA, whereas the proinsulin to insulin ratio was inversely correlated with BW SDS. The proinsulin to insulin ratio was raised (P = 0.002) in fetuses with UV PO₂ less than or equal to 21.3 mm Hg (i.e. the 50th percentile) compared with those with PO₂ more than 21.3 mm Hg, inferring that in utero hypoxia engenders ß-cell secretory dysfunction. Proinsulin, insulin, and C-peptide were markedly but transiently (<24 h) elevated after maternal betamethasone administration, returning thereafter to concentrations measured in noncorticosteroid-treated fetuses. However, there was considerable variability within the less than 24-h betamethasone group: the indices of insulin secretion were related to UV PO₂, suggesting that hypoxia attenuates the responsiveness of fetal ß-cells to corticosteroids. Adiponectin was not related to any of the insulin indices.

In conclusion, we have identified two environmental signals that modulate fetal insulin output: maternal corticosteroids produce a transient surge in fetal insulin synthesis and secretion, whereas in utero hypoxia disturbs the insulin secretory process.

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