Oestrogens Improve Human Pancreatic Islet Transplantation in a Mouse Model of Insulin Deficient Diabetes

Diabetologia. 2013 Feb;56(2):370-81. doi: 10.1007/s00125-012-2764-1. Epub 2012 Nov 7.

Abstract

Aims/hypothesis: Pancreatic islet transplantation (PIT) offers a physiological treatment for type 1 diabetes, but the failure of islet engraftment hinders its application. The female hormone 17β-oestradiol (E2) favours islet survival and stimulates angiogenesis, raising the possibility that E2 may enhance islet engraftment following 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Blood Glucose / drug effects
  • Estrogen Receptor alpha / agonists
  • Estrogen Receptor beta / agonists
  • Estrogens / pharmacology*
  • Ginsenosides / pharmacology
  • Graft Survival / drug effects
  • Humans
  • Immunohistochemistry
  • Islets of Langerhans Transplantation*
  • Male
  • Mice
  • Mice, Nude
  • Nitriles / pharmacology
  • Propionates / pharmacology
  • Sapogenins / pharmacology

Substances

  • Blood Glucose
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Estrogens
  • Ginsenosides
  • Nitriles
  • Propionates
  • Sapogenins
  • diarylpropionitrile
  • ginsenoside 20S-protopanaxatriol