Enzymatically stable analogue of the gut‐derived peptide xenin on beta‐cell transdifferentiation in high fat fed and insulin‐deficient Ins1Cre/+;Rosa26‐eYFP mice

Abstract

Background The antidiabetic effects of the gut hormone xenin include augmenting insulin secretion and positively affecting pancreatic islet architecture. Methods The current study has further probed pancreatic effects through sub‐chronic administration of the long‐acting xenin analogue, xenin‐25[Lys¹³PAL], in both high fat fed (HFF) and streptozotocin (STZ)‐induced insulin‐deficient Ins1 ^Cre/+;Rosa26‐eYFP transgenic mice. Parallel effects on metabolic control and pancreatic islet morphology, including islet beta‐cell lineage tracing were also assessed. Results Xenin‐25[Lys¹³PAL] treatment reversed body weight loss induced by STZ, increased plasma insulin and decreased blood glucose levels. There were less obvious effects on these parameters in HFF mice, but all xenin‐25[Lys¹³PAL] treated mice exhibited decreased pancreatic alpha‐cell areas and circulating glucagon. Xenin‐25[Lys¹³PAL] treatment fully, or partially, returned overall islet and beta‐cell areas in STZ‐ and HFF mice to those of lean control animals, respectively, and was consistently associated with decreased beta‐cell apoptosis. Interestingly, xenin‐25[Lys¹³PAL] also increased beta‐cell proliferation and decreased alpha‐cell apoptosis in STZ mice, with reduced alpha‐cell growth noted in HFF mice. Lineage tracing studies revealed that xenin‐25[Lys¹³PAL] reduced the number of insulin positive pancreatic islet cells that lost their beta‐cell identity, in keeping with a decreased transition of insulin positive to glucagon positive cells. These beneficial effects on islet cell differentiation were linked to maintained expression of Pdx1 within beta‐cells. Xenin‐25[Lys¹³PAL] treatment was also associated with increased numbers of smaller sized islets in both models. Conclusion Benefits of xenin‐25[Lys¹³PAL] on diabetes includes positive modulation of islet cell differentiation, in addition to promoting beta‐cell growth and survival.