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 weeks and birth weight standard-deviation-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/insulin-ratio as a measure of -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/insulin-ratio was inversely correlated with BW-SDS. The proinsulin/insulin ratio was raised (P = 0.002) in fetuses with UV PO₂ 21.3 mm Hg (i.e. the 50^th percentile) compared with those with PO₂ >21.3 mm Hg, inferring that in utero hypoxia engenders -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 non-corticosteroid-treated fetuses. But there was considerable variability within the <24 h-betamethasone group: the indices of insulin secretion were related to UV PO₂, suggesting that hypoxia attenuates the responsiveness of fetal -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.