Effect of Multiparity on Pregnancy-Induced Islet Adaptation and Cellular Transdifferentiation

Background: Pregnancy induces a reversible expansion of pancreatic islet and beta-cell mass, but the impact of multiple pregnancies on these processes remains unclear. Methods: To further investigate this phenomenon, the current study employed transgenic models with beta- or alpha-cell lineage tracing capabilities, namely Ins1 Cre/+ ;Rosa26-eYFP and Glu CreERT2 ;Rosa26-eYFP male mice, respectively. Using these models, we explored late-stage morphological islet adaptations and cellular plasticity in response to primi-, bi- and tri-parity. Results: All pregnant mice exhibited augmented islet and beta-cell areas, associated with decreased beta-cell apoptosis and increased proliferation. Notably, beta-cell proliferative capacity decreased as parity increased, but was still elevated in triparous mice when compared to null parous controls. Interestingly, alpha-cells also exhibited augmented growth and survival in all pregnant mice. In terms of cellular transdifferentiation, ductal to beta-cell conversion appeared greater in primiparous Ins1 Cre/+ ;Rosa26-eYFP mice, but was much less obvious in bi- and tri-parous mice. Whilst quantification of beta- to alpha-cell transition events was more pronounced during pregnancy, it was less obvious in multiparity than primiparity. There were also notable reductions in beta-cell dedifferentiation, supporting positive effects of islet cell plasticity towards retention and expansion of beta-cell mass in multiparity. In harmony, alpha- to beta-cell transdifferentiation appeared markedly increased in multiparous Glu CreERT2 ;Rosa26-eYFP mice, coupled with augmented alpha-cell neogenesis and dedifferentiation, suggesting that these cells act as a principal source for beta-cell expansion. Conclusion: Together, these findings indicate that reduced beta-cell proliferation in multiparity is offset by enhanced islet cell plasticity, contributing to sustained islet adaptation across multiple gestations.