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

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[Lys ¹³PAL], 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[Lys ¹³PAL] 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[Lys ¹³PAL] treated mice exhibited decreased pancreatic alpha-cell areas and circulating glucagon. Xenin-25[Lys ¹³PAL] 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[Lys ¹³PAL] 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[Lys ¹³PAL] 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[Lys ¹³PAL] treatment was also associated with increased numbers of smaller sized islets in both models. Conclusions: Benefits of xenin-25[Lys ¹³PAL] on diabetes includes positive modulation of islet cell differentiation, in addition to promoting beta-cell growth and survival.