Adverse effect of age on pancreatic islet morphology, islet cell turnover and lineage-labelled hormone expression in mice

Ageing leads to a gradual decline in the structure and function of many bodily organs, including the endocrine pancreas. The current study examines the impact of ageing on pancreatic islet morphology, and especially the role of islet cell plasticity in this process. Transgenic Ins1Cre/+;Rosa26-eYFP mice, with islet beta-cell tracing capabilities, were employed at 12 and 52 weeks of age, and islet morphology, islet cell turnover as well as changes in beta-cell identity and plasticity assessed. Ageing was associated with elevated body weight and circulating glucose levels. There was also substantial remodelling of pancreatic islet morphology in 52-week-old mice, that included a notable decrease of islet number as well as overall islet, alpha- and beta-cell areas. This was associated with diminished beta-cell proliferation and survival, but interestingly alpha-cell proliferation was increased in older mice, as was the number of islet cells positive for both insulin and glucagon. There was increased loss of insulin expression in original GFP labelled islet cells in older Ins1Cre/+;Rosa26-eYFP mice complemented by augmented glucagon and GFP co-positive cell numbers. Observations in GluCreERT2;ROSA26-eYFP transgenic mice, with alpha-cell tracing technologies, demonstrated reduced numbers of lineage-labelled alpha-cells co-expressing insulin. Furthermore, the ability of pancreatic ductal cells to assume an islet beta-cell phenotype was impaired in older Ins1Cre/+;Rosa26-eYFP mice. These findings demonstrate an age-related deterioration of pancreatic islet morphology, linked in part to altered patterns of lineage-labelled hormone expression alongside changes in islet cell turnover.