This is the resubmission of the first competitive renewal of R01DK074970 """"""""Role of estrogen receptors in beta- cell survival and insulin secretion"""""""". Our laboratory was a pioneer in demonstrating that the female hormone 17?-estradiol (E2) protects islet ?-cells from apoptosis in vivo in mice. We have shown that E2 anti-apoptotic protection is mediated via extranuclear estrogen receptor (ER)s. We also reported that activation of these ERs enhances islet insulin biosynthesis and prevents islet lipotoxicity in vivo thus preventing ?-cell failure in rodent models of type 2 diabetes. This competitive renewal focuses on the role of ERs in pancreatic islet engraftment during transplantation in insulin deficient diabetes. Pancreatic islet transplantation (PIT) is an important therapeutic approach in type 1 diabetes (T1D). However, the failure of islet revascularization and engraftment limits its widespread application. The transplanted islets exposed to multiple insults may be destroyed before revascularization occurs. Our new preliminary data suggest that ER activation permanently improves human islet engraftment during PIT in a mouse model of T1D via multiple mechanisms involving an acute suppression of islet graft hypoxia and apoptosis and an acute suppression of hyperglucagonemia. This is associated to a latter increase in islet revascularization and functional mass. In this application we propose to explore the contributions of the ER? in graft ?-cells, recipient ?-cells and endothelial cells to islet revascularization during PIT, using mice with conditional null alleles of ER? in these cells. We also propose to explore the synergy between estrogen and glucagon-like peptide-1 (GLP-1) in human islet survival and revascularization in a diabetic mouse model of PIT using a novel compound combining E2 and GLP-1 in a single molecule which allows the targeting of E2 where membrane GLP-1 receptors are present, the ?-cells and the endothelial cells, and away from gynecological tissues.

Public Health Relevance

The research proposed in this grant will have a significant impact because when successfully completed it will provide a rapidly available therapeutic alternative to improve pancreatic islet engraftment in type 1 diabetic patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Appel, Michael C
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Zhang, Yanqing; Fava, Genevieve E; Wang, Hongjun et al. (2016) PAX4 Gene Transfer Induces α-to-β Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment. Mol Ther 24:251-60
Mauvais-Jarvis, Franck (2016) Androgen-deprivation therapy and pancreatic β-cell dysfunction in men. J Diabetes Complications 30:389-90
Navarro, Guadalupe; Xu, Weiwei; Jacobson, David A et al. (2016) Extranuclear Actions of the Androgen Receptor Enhance Glucose-Stimulated Insulin Secretion in the Male. Cell Metab 23:837-51
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Mauvais-Jarvis, Franck (2016) Role of Sex Steroids in β Cell Function, Growth, and Survival. Trends Endocrinol Metab :
Mauvais-Jarvis, Franck (2015) Elucidating sex and gender differences in diabetes: a necessary step toward personalized medicine. J Diabetes Complications 29:162-3
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Navarro, Guadalupe; Allard, Camille; Xu, Weiwei et al. (2015) The role of androgens in metabolism, obesity, and diabetes in males and females. Obesity (Silver Spring) 23:713-9
Hevener, Andrea L; Clegg, Deborah J; Mauvais-Jarvis, Franck (2015) Impaired estrogen receptor action in the pathogenesis of the metabolic syndrome. Mol Cell Endocrinol 418 Pt 3:306-21
Kilic, Gamze; Alvarez-Mercado, Ana I; Zarrouki, Bader et al. (2014) The islet estrogen receptor-α is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes. PLoS One 9:e87941

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