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.
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.
|Kilic, Gamze; Alvarez-Mercado, Ana I; Zarrouki, Bader et al. (2014) The islet estrogen receptor-? is induced by hyperglycemia and protects against oxidative stress-induced insulin-deficient diabetes. PLoS One 9:e87941|
|Bernal-Mizrachi, Ernesto; Kulkarni, Rohit N; Scott, Donald K et al. (2014) Human ?-cell proliferation and intracellular signaling part 2: still driving in the dark without a road map. Diabetes 63:819-31|
|Nohara, Kazunari; Laque, Amanda; Allard, Camille et al. (2014) Central mechanisms of adiposity in adult female mice with androgen excess. Obesity (Silver Spring) 22:1477-84|
|Nohara, Kazunari; Waraich, Rizwana S; Liu, Suhuan et al. (2013) Developmental androgen excess programs sympathetic tone and adipose tissue dysfunction and predisposes to a cardiometabolic syndrome in female mice. Am J Physiol Endocrinol Metab 304:E1321-30|
|Liu, S; Kilic, G; Meyers, M S et al. (2013) Oestrogens improve human pancreatic islet transplantation in a mouse model of insulin deficient diabetes. Diabetologia 56:370-81|
|Nohara, Kazunari; Liu, Suhuan; Meyers, Matthew S et al. (2013) Developmental androgen excess disrupts reproduction and energy homeostasis in adult male mice. J Endocrinol 219:259-68|
|Mauvais-Jarvis, Franck (2013) Novel link between inflammation, endothelial dysfunction, and muscle insulin resistance. Diabetes 62:688-90|
|Tiano, Joseph P; Mauvais-Jarvis, Franck (2012) Importance of oestrogen receptors to preserve functional ?-cell mass in diabetes. Nat Rev Endocrinol 8:342-51|
|Tiano, Joseph; Mauvais-Jarvis, Franck (2012) Selective estrogen receptor modulation in pancreatic ýý-cells and the prevention of type 2 diabetes. Islets 4:173-6|
|Nohara, Kazunari; Zhang, Yan; Waraich, Rizwana S et al. (2011) Early-life exposure to testosterone programs the hypothalamic melanocortin system. Endocrinology 152:1661-9|
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