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Diabetologia
Published in: Diabetologia 2/2013

Open Access 01-02-2013 | Article

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

Authors: S. Liu, G. Kilic, M. S. Meyers, G. Navarro, Y. Wang, J. Oberholzer, F. Mauvais-Jarvis

Published in: Diabetologia | Issue 2/2013

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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.
Appendix
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Literature
1.
Shapiro AM, Lakey JR, Ryan EA et al (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230–238PubMedCrossRef
2.
Hering BJ, Kandaswamy R, Ansite JD et al (2005) Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA 293:830–835PubMedCrossRef
3.
Shapiro AM, Ricordi C, Hering BJ et al (2006) International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330PubMedCrossRef
4.
Robertson RP (2010) Islet transplantation a decade later and strategies for filling a half-full glass. Diabetes 59:1285–1291PubMedCrossRef
5.
Weir GC, Bonner-Weir S (2004) Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 53(Suppl 3):S16–S21
6.
Davalli AM, Ogawa Y, Ricordi C, Scharp DW, Bonner-Weir S, Weir GC (1995) A selective decrease in the beta cell mass of human islets transplanted into diabetic nude mice. Transplantation 59:817–820PubMed
7.
Davalli AM, Scaglia L, Zangen DH, Hollister J, Bonner-Weir S, Weir GC (1996) Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function. Diabetes 45:1161–1167PubMedCrossRef
8.
Emamaullee JA, Shapiro AM (2006) Interventional strategies to prevent beta-cell apoptosis in islet transplantation. Diabetes 55:1907–1914PubMedCrossRef
9.
Carlsson PO, Palm F, Andersson A, Liss P (2001) Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site. Diabetes 50:489–495PubMedCrossRef
10.
Mattsson G, Jansson L, Carlsson PO (2002) Decreased vascular density in mouse pancreatic islets after transplantation. Diabetes 51:1362–1366PubMedCrossRef
11.
Contreras JL, Smyth CA, Bilbao G, Young CJ, Thompson JA, Eckhoff DE (2002) 17beta-Estradiol protects isolated human pancreatic islets against proinflammatory cytokine-induced cell death: molecular mechanisms and islet functionality. Transplantation 74:1252–1259PubMedCrossRef
12.
Le May C, Chu K, Hu M et al (2006) Estrogens protect pancreatic beta-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Natl Acad Sci USA 103:9232–9237PubMedCrossRef
13.
Liu S, Le May C, Wong WP et al (2009) Importance of extranuclear estrogen receptor-alpha and membrane G protein-coupled estrogen receptor in pancreatic islet survival. Diabetes 58:2292–2302PubMedCrossRef
14.
Wong WP, Tiano JP, Liu S et al (2010) Extranuclear estrogen receptor-alpha stimulates NeuroD1 binding to the insulin promoter and favors insulin synthesis. Proc Natl Acad Sci USA 107:13057–13062PubMedCrossRef
15.
Liu S, Mauvais-Jarvis F (2010) Minireview: estrogenic protection of beta-cell failure in metabolic diseases. Endocrinology 151:859–864PubMedCrossRef
16.
Alonso-Magdalena P, Ropero AB, Carrera MP et al (2008) Pancreatic insulin content regulation by the estrogen receptor ER alpha. PLoS One 3:e2069PubMedCrossRef
17.
Tiano JP, Delghingaro-Augusto V, Le May C et al (2011) Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents beta cell failure in rodent models of type 2 diabetes. J Clin Invest 121:3331–3342PubMedCrossRef
18.
Tiano JP, Mauvais-Jarvis F (2012) Importance of oestrogen receptors to preserve functional beta-cell mass in diabetes. Nat Rev Endocrinol 8:342–351
19.
Shifren JL, Tseng JF, Zaloudek CJ et al (1996) Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis. J Clin Endocrinol Metab 81:3112–3118PubMedCrossRef
20.
Mueller MD, Vigne JL, Minchenko A, Lebovic DI, Leitman DC, Taylor RN (2000) Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proc Natl Acad Sci USA 97:10972–10977PubMedCrossRef
21.
Losordo DW, Isner JM (2001) Estrogen and angiogenesis: a review. Arterioscler Thromb Vasc Biol 21:6–12PubMedCrossRef
22.
Morales DE, McGowan KA, Grant DS et al (1995) Estrogen promotes angiogenic activity in human umbilical vein endothelial cells in vitro and in a murine model. Circulation 91:755–763PubMedCrossRef
23.
Mendelsohn ME, Karas RH (1999) The protective effects of estrogen on the cardiovascular system. N Engl J Med 340:1801–1811PubMedCrossRef
24.
Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M (2000) Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 127:4277–4291PubMed
25.
Molano RD, Pileggi A, Berney T et al (2003) Long-term islet allograft survival in nonobese diabetic mice treated with tacrolimus, rapamycin, and anti-interleukin-2 antibody. Transplantation 75:1812–1819PubMedCrossRef
26.
Olsson R, Olerud J, Pettersson U, Carlsson PO (2011) Increased numbers of low-oxygenated pancreatic islets after intraportal islet transplantation. Diabetes 60:2350–2353PubMedCrossRef
27.
Chen C, Kuehn C, Bretzel RG, Linn T (2009) Anti-inflammatory thalidomide improves islet grafts survival and functions in a xenogenic environment. PLoS One 4:e6312PubMedCrossRef
28.
Armstrong D, Browne R (1994) The analysis of free radicals, lipid peroxides, antioxidant enzymes and compounds related to oxidative stress as applied to the clinical chemistry laboratory. Adv Exp Med Biol 366:43–58PubMedCrossRef
29.
Moos WH, Dykens JA, Howell N (2008) 17α-Estradiol: a less-feminizing estrogen. Drug Dev Res 69:177–184
30.
Stauffer SR, Coletta CJ, Tedesco R et al (2000) Pyrazole ligands: structure-affinity/activity relationships and estrogen receptor-alpha-selective agonists. J Med Chem 43:4934–4947PubMedCrossRef
31.
Meyers MJ, Sun J, Carlson KE, Marriner GA, Katzenellenbogen BS, Katzenellenbogen JA (2001) Estrogen receptor-beta potency-selective ligands: structure-activity relationship studies of diarylpropionitriles and their acetylene and polar analogues. J Med Chem 44:4230–4251PubMedCrossRef
32.
Bologa CG, Revankar CM, Young SM et al (2006) Virtual and biomolecular screening converge on a selective agonist for GPR30. Nat Chem Biol 2:207–212PubMedCrossRef
33.
Brissova M, Fowler M, Wiebe P et al (2004) Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. Diabetes 53:1318–1325PubMedCrossRef
34.
Nyqvist D, Kohler M, Wahlstedt H, Berggren PO (2005) Donor islet endothelial cells participate in formation of functional vessels within pancreatic islet grafts. Diabetes 54:2287–2293PubMedCrossRef
35.
Zhang N, Su D, Qu S et al (2006) Sirolimus is associated with reduced islet engraftment and impaired beta-cell function. Diabetes 55:2429–2436PubMedCrossRef
36.
Kang L, Zhang X, Xie Y et al (2010) Involvement of estrogen receptor variant ER-alpha36, not GPR30, in nongenomic estrogen signaling. Mol Endocrinol 24:709–721PubMedCrossRef
37.
Kuebler JF, Jarrar D, Toth B et al (2002) Estradiol administration improves splanchnic perfusion following trauma-hemorrhage and sepsis. Arch Surg 137:74–79PubMedCrossRef
38.
Dobbs R, Sakurai H, Sasaki H et al (1975) Glucagon: role in the hyperglycemia of diabetes mellitus. Science 187:544–547PubMedCrossRef
39.
Raskin P, Unger RH (1978) Hyperglucagonemia and its suppression. Importance in the metabolic control of diabetes. N Engl J Med 299:433–436PubMedCrossRef
40.
Unger RH, Cherrington AD (2012) Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 122:4–12PubMedCrossRef
41.
Lee Y, Wang MY, Du XQ, Charron MJ, Unger RH (2011) Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 60:391–397PubMedCrossRef
42.
Yu X, Park BH, Wang MY, Wang ZV, Unger RH (2008) Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci USA 105:14070–14075PubMedCrossRef
43.
Maruyama H, Hisatomi A, Orci L, Grodsky GM, Unger RH (1984) Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest 74:2296–2299PubMedCrossRef
44.
Kawamori D, Kurpad AJ, Hu J et al (2009) Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metabolism 9:350–361PubMedCrossRef
45.
Eckhoff DE, Eckstein C, Smyth CA et al (2004) Enhanced isolated pancreatic islet recovery and functionality in rats by 17β-estradiol treatment of brain death donors. Surgery 136:336–345PubMedCrossRef
46.
Ma XL, Gao F, Chen J et al (2001) Endothelial protective and antishock effects of a selective estrogen receptor modulator in rats. Am J Physiol Heart Circ Physiol 280:H876–H884PubMed
47.
Vacca G, Battaglia A, Grossini E, Mary DA, Molinari C, Surico N (1999) The effect of 17beta-oestradiol on regional blood flow in anaesthetized pigs. J Physiol 514:875–884PubMedCrossRef
48.
Salonia A, Lanzi R, Scavini M et al (2006) Sexual function and endocrine profile in fertile women with type 1 diabetes. Diabetes Care 29:312–316PubMedCrossRef
Metadata
Title
Oestrogens improve human pancreatic islet transplantation in a mouse model of insulin deficient diabetes
Authors
S. Liu
G. Kilic
M. S. Meyers
G. Navarro
Y. Wang
J. Oberholzer
F. Mauvais-Jarvis
Publication date
01-02-2013
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 2/2013
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-012-2764-1

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