Impact of Sex on Age-Related Changes in Pancreatic Islet Morphology and Beta-Cell Plasticity in Mice

The aim of the current study was to assess the impact of age and sex on pancreatic islet morphology and related islet cell lineage. To accomplish this, virgin male and female transgenic Ins1Cre/+;Rosa26-eYFP and GluCreERT2;ROSA26-eYFP mice were employed at 12 and 52 weeks of age, with sex- and age-dependent effects on pancreatic islet structure, and particularly the influence of changes in islet cell plasticity, examined. At 12 weeks of age, male Ins1Cre/+;Rosa26-eYFP mice exhibited increases in overall pancreatic islet area and number, as well as alpha- and beta-cell areas when compared to similarly aged females. This was associated with reduced beta-cell apoptosis and a preservation of beta-cell identity, alongside a prominent increase in the association of ductal and beta-cell markers. However, at 52 weeks of age, there was an almost complete sex-specific reversal of effects on islet morphology. Older female mice presented with enhanced islet- and beta-cell area when compared to respective males, which was accompanied by substantially reduced beta-cell apoptosis rates, up-regulated beta-cell neogenesis, plus markedly reduced beta-cell dedifferentiation. Observations in related GluCreERT2;ROSA26-eYFP transgenic mice further highlighted the promotion of islet cell transitioning events in female mice that encourage preservation of beta-cell mass in response to ageing. In conclusion, there are clear sex- and age-provoked differences in pancreatic islet morphology. Such changes are partly linked to modification of islet cell turnover rates, and especially the ability of female, but not male, mice to effectively modify islet cell plasticity towards retention of beta-cell mass in the face of age-induced stress.