II. Adaptive β-cell response in pregnancy and during weaning

A. β-Cell mass expansion of pregnancy

During the third trimester of pregnancy, increased insulin resistance in the mother maintains nutrient flow to the growing fetus, while maternal β-cell mass is expanded (by 1.5 at least) in order to counterbalance the resistance and prevent hypoglycemia (Michael German lecture). Lactogenic hormones, prolactin and placental lactogen, are known to drive the expansion of insulin-producing β cells,⁵ which precedes the drop in maternal insulin sensitivity. Kim et al showed that serotonin acts downstream of lactogen signaling to drive β-cell proliferation during pregnancy, through the drastic upregulation of serotonin synthetic enzyme Tph1.6 Consistently the blockade of Htr2b (serotonin receptor in islets) in pregnant mice blocks β-cell expansion and causes glucose intolerance. Interestingly, when human islets are transplanted in pregnant mice, no β-cell proliferation is seen, while mouse β-cell mass expands. If human islets are transplanted in one mouse kidney cap, and human placental cells (trophoblasts) in the other, then human β-cell proliferation is observed. These experiments
lead to the conclusion that exosomes are secreted by the placenta and contain species-specific miRNA (microRNAs, small strands of RNA that mediate posttranscriptional gene silencing), mRNA, and proteins that act on β-cell proliferation (Michael German lecture). German et al showed earlier that the expression of a unique profile of miRNAs is required for β-cell formation during pancreas development.7

B. Postnatal β-cell maturation

Fetal β-cells (from Ngn3+ progenitors) are poorly responsive to glucose, and glucosestimulated insulin secretion increases gradually after birth, while β-cell proliferation decreases with age (Maike Sanders lecture). Stolovich-Rain et al showed that weaning triggers a discrete maturation step of β cells, elevating the mitogenic and secretory responses to glucose. The molecular characterization of β-cell maturation has shown the involvement of the transcription factors MafA, Pdx1, and NeuroD1 as well as thyroid hormone, and has identified urocortin 3 as a marker of the process (review by Stolovich-Rain et al).⁸