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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK074970-08
Application #
8730619
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2007-04-15
Project End
2015-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Tulane University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Li, Jianzhuo; Fu, Xueqi; Cao, Subing et al. (2018) Membrane-associated androgen receptor (AR) potentiates its transcriptional activities by activating heat shock protein 27 (HSP27). J Biol Chem 293:12719-12729
Zhou, Zhenqi; Ribas, Vicent; Rajbhandari, Prashant et al. (2018) Estrogen receptor ? protects pancreatic ?-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress. J Biol Chem 293:4735-4751
Xu, Beibei; Allard, Camille; Alvarez-Mercado, Ana I et al. (2018) Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes. Cell Rep 24:181-196
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Mukerjee, Snigdha; Zhu, Yun; Zsombok, Andrea et al. (2018) Perinatal Exposure to Western Diet Programs Autonomic Dysfunction in the Male Offspring. Cell Mol Neurobiol 38:233-242
Sharma, Geetanjali; Mauvais-Jarvis, Franck; Prossnitz, Eric R (2018) Roles of G protein-coupled estrogen receptor GPER in metabolic regulation. J Steroid Biochem Mol Biol 176:31-37
Morford, Jamie J; Wu, Sheng; Mauvais-Jarvis, Franck (2018) The impact of androgen actions in neurons on metabolic health and disease. Mol Cell Endocrinol 465:92-102
Pollock, Benjamin D; Chen, Wei; Harville, Emily W et al. (2018) Differential sex effects of systolic blood pressure and low-density lipoprotein cholesterol on type 2 diabetes: Life course data from the Bogalusa Heart Study. J Diabetes 10:449-457

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