Enzymatically stable analogue of the gut‐derived peptide xenin on beta‐cell transdifferentiation in high fat fed and insulin‐deficient Ins1^Cre/+;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 Ins1Cre/+;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. Conclusions Benefits of xenin‐25[Lys13PAL] on diabetes includes positive modulation of islet cell differentiation, in addition to promoting beta‐cell growth and survival.

Weight‐reducing, lipid‐lowering and antidiabetic activities of a novel arginine vasopressin analogue acting at the V1a and V1b receptors in high‐fat‐fed mice

“…In relation to this, there was a reduction in islet‐ and beta‐cell areas, as well as pancreatic insulin content, in both treatment groups of HFF mice, accompanied by decreased proliferation of both alpha and beta cells. Thus, changes in islet‐cell proliferation rates, or in recently reported islet cell transitioning events, 44 probably outweigh decreased beta‐cell apoptosis observed with both peptides. Moreover, GLP‐1 receptor signalling has recently been linked to positive effects on alpha‐ and beta‐cell transdifferentiation 45 .…”

Xenin and Related Peptides: Potential Therapeutic Role in Diabetes and Related Metabolic Disorders

“… 76 Remarkably, the same study also demonstrated long-acting positive metabolic effects of (DAla 2 )GIP/xenin-8-Gln following 14-day cessation of treatment. 76 This could suggest positive metabolic reprogramming induced by co-activation of GIP and xenin receptor pathways in keeping with positive effects on beta cell function and integrity, 6 , 29 , 43 and represents a potential benefit for future antidiabetic therapy. Such observations are extremely important moving towards the clinical setting given the complex aetiology and progressive nature of type 2 diabetes mellitus in humans.…”

“… 27 However, effects of xenin independent of neurotensin receptor activation have been demonstrated, 28 highlighting the need for further detailed studies in this area. Finally, although there is no direct evidence for xenin induced benefits in type 1 diabetes mellitus, reduction of beta-cell apoptosis 10 alongside positive actions on islet cell transdifferentiation, 29 could be suggestive of positive effects of xenin in this disease state.…”

“…Moreover, recent studies in insulin-deficient Ins1 Cre/+ ; Rosa26-eYFP transgenic mice with islet cell lineage tracing capabilities reveal positive effects of xenin on islet cell differentiation, including maintenance of beta cell identity and prevention of beta cell de-differentiation. 29 These positive effects on islet cell architecture may be related to potentiation of the biological actions of GIP, since GIP has established benefits on beta cell growth and survival, as well as transdifferentiation. 40 - 43 The mechanisms related to these xenin-mediated pancreatic islet actions are somewhat disputed however, with proposed importance of both direct and indirect actions.…”

Beneficial impact of Ac3IV, an AVP analogue acting specifically at V1a and V1b receptors, on diabetes islet morphology and transdifferentiation of alpha- and beta-cells

“…In the present study, we used transgenic mice with beta-cell lineage tracing capabilities, to investigate the impact of transdifferentiation of beta- to alpha-cells in Ac3IV-induced improvements of pancreatic islet architecture in diabetes. Fully characterised transgenic Ins1 Cre/+ ; Rosa26-eYFP mice were utilised [ 10 , 11 , 13 , 14 , 16 ], alongside induction of diabetes and islet damage by multiple low dose streptozotocin (STZ) administration. The subsequent impact of 12 days pharmacological upregulation of V1a and V1b receptor pathways by Ac3IV on beta-cell lineage was then studied.…”