Oestrogens improve human pancreatic islet transplantation in a mouse model of insulin deficient diabetes

Abstract

Aims/hypothesisPancreatic 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.MethodsTo 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.ResultsTreatment 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/interpretationDuring 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-012-2764-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

GPER1 is regulated by insulin in cancer cells and cancer-associated fibroblasts

“…Indeed, GPER1 has been implicated not only in cancer, but also in cardiovascular, immunological, and neurological functions as well as diabetes (Mizukami 2010). GPER1 has been proposed as an interesting therapeutic target in diabetes and pancreatic islet transplantation (Mårtensson et al 2009, Liu et al 2013. Accordingly, GPER1 has been detected in pancreatic b-cells and GPER1 ligands have shown insulinotropic effects by mediating pancreatic b-cell survival and stimulating insulin release (Liu et al 2009, Balhuizen et al 2010.…”

Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes

“…CE prevention of β cell failure in Akita mice could be partially mediated via non-islet cells effects easing the metabolic stress on β cells. However, extensive evidence demonstrates that estrogens protect β cell survival and function in vivo in rodents and cultured human islets via direct effect on ERα in β cells (Kilic et al, 2014; Le May et al, 2006; Liu et al, 2009, 2013; Tiano et al, 2011; Tiano and Mauvais-Jarvis, 2012; Wong et al, 2010). Therefore, it is likely that in the Akita model of pure insulin deficiency, CE prevent diabetes via a direct β cell effect preventing ER stress.…”

“…The female hormone 17β-estradiol (E 2 ) protects rodent β cells in vivo against multiple proapoptotic insults (Kilic et al, 2014; Le May et al, 2006; Liu et al, 2009, 2013; Liu and Mauvais-Jarvis, 2009; Tiano et al, 2011; Tiano and Mauvais-Jarvis, 2012; Wong et al, 2010), and this protection is conserved in human islets (Kilic et al, 2014; Liu et al, 2009, 2013; Liu and Mauvais-Jarvis, 2009; Tiano et al, 2011; Tiano and Mauvais-Jarvis, 2012; Wong et al, 2010). That E 2 action in β cells prevents apoptosis induced by excess lipids and glucose, oxidative stress, and proinflammatory cytokines—all conditions producing ER stress and activating the UPR (Wang and Kaufman, 2016)—led us to envision a unifying mechanism in which activation of estrogen receptors (ERs) in β cells mitigates ER stress and helps resolve the UPR.…”

What have we learned about GPER function in physiology and disease from knockout mice?

“…Estrogen exhibits numerous important effects in the pancreas, including stimulating insulin synthesis [143, 144] and secretion [145, 146], enhancing β-cell survival [11, 147] and islet survival following transplantation [148], and reducing lipotoxicity [142, 149]. In 2009, Mauvais-Jarvis and colleagues employed a streptozotocin-induced model of type 1 diabetes with ERα, ERβ and GPER KO mice to demonstrate that both ERα and GPER mediated pancreatic islet survival [82].…”

“…Specifically, female GPER KO1 mice exhibited a loss in protection from streptozotocin-induced diabetes by endogenous estrogens and the GPER-selective agonist G-1 protected from ROS-induced apoptosis as effectively as estrogen in both murine and human islets, with the protective effect of G-1 absent in islets isolated from GPER KO1 mice [82]. Furthermore, G-1, as well as ERα- and ERβ-selective estrogenic ligands, increase survival of human islets following xenotransplantation into mice, but only the ER-selective ligands improved islet revascularization [148]. …”