Conclusions/interpretation
During PIT, E2 synergistic actions contribute to enhancing human islet-graft survival, revascularisation and functional mass. This study identifies E2 as a short-term treatment to improve PIT.
Methods
To explore this hypothesis, we used an insulin-deficient model with xenotransplantation of a marginal dose of human islets in nude mice rendered diabetic with streptozotocin. This was followed by 4 weeks of treatment with vehicle, E2, the non-feminising oestrogen 17α-oestradiol (17α-E2), the oestrogen receptor (ER) α agonist propyl-pyrazole-triol (PPT), the ERβ agonist diarylpropionitrile (DPN) or the G protein-coupled oestrogen receptor (GPER) agonist G1.
Results
Treatment with E2, 17α-E2, PPT, DPN or G1 acutely improved blood glucose and eventually promoted islet engraftment, thus reversing diabetes. The effects of E2 were retained in the presence of immunosuppression and persisted after discontinuation of E2 treatment. E2 produced an acute decrease in graft hypoxic damage and suppressed beta cell apoptosis. E2 also acutely suppressed hyperglucagonaemia without altering insulin secretion, leading to normalisation of blood glucose. Conclusions/interpretation: During PIT, E2 synergistic actions contribute to enhancing human islet-graft survival, revascularisation and functional mass. This study identifies E2 as a short-term treatment to improve PIT.