In diabetes, the death of insulin-producing ?-cells in the ? pancreas by apoptosis leads to insulin dependence. Yet, the events that promote ?-cell death are still ? not fully understood. It is essential to increase our basic knowledge of the processes regulating ?-cell ? survival in order to develop novel and efficient therapies for diabetic patients. Evidence suggests that ? the female hormone, 17?-estradiol (estradiol), protects insulin production and prevents diabetes. ? Although estradiol acts primarily via two distinct estrogen receptors (ERs), ERa and ER?, the individual ? contributions of these ERs in protecting ?-cell survival have not been established. Our long-term goal is ? to determine how to protect insulin production in diabetic patients by modulating estrogen signaling ? pathways in a gender non-specific manner. Our objective for this application is to elucidate the ? respective roles played by ERa, ER?, and non-classical estrogen actions in ?-cell survival and insulin ? production in vivo, through the use of genetic mouse models. Based on the preliminary data we have ? generated, our hypothesis is that ERa protects ?-cell survival; whereas, ER? reduces ERa function and ? provokes ?-cell apoptosis. In order to test this hypothesis, we will first use a ?-cell ERa deficient mouse ? (?ERaKO) to demonstrate that selective elimination of ERa in ?-cells impairs insulin production and ? provokes diabetes. Next, we will study a ?-cell ER? deficient mouse (?ER?KO) to demonstrate that ? conversely, selective elimination of ER? in ?-cells improves insulin production and prevents diabetes. ? Finally, we will create a combined ?-cell specific ERa/ER? knockout mouse (?ERa?KO). Using this last ? model we will demonstrate that in absence of the classical ERa and ER? in ?-cells, estradiol protects ? insulin production and prevents diabetes via non-genomic actions involving a novel membrane ER. ? Through the proposed research - which is the first investigation of ERs in ?-cell survival in vivo - we ? plan to demonstrate that classical and non-classical estrogen receptors are important to ?-cell survival ? in vivo, and therefore represent viable targets for therapeutic intervention. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK074970-01A2
Application #
7268242
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Appel, Michael C
Project Start
2007-04-15
Project End
2012-03-31
Budget Start
2007-04-15
Budget End
2008-03-31
Support Year
1
Fiscal Year
2007
Total Cost
$279,350
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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
Gautier, Jean-Fran├žois; Fetita, Lila Sabrina; Riveline, Jean-Pierre et al. (2018) Sex Difference In the Effect of Fetal Exposure to Maternal Diabetes on Insulin Secretion. J Endocr Soc 2:391-397
Mauvais-Jarvis, Franck (2018) Gender differences in glucose homeostasis and diabetes. Physiol Behav 187:20-23
Zimmerman, Margaret A; Hutson, Dillion D; Mauvais-Jarvis, Franck et al. (2018) Bazedoxifene-induced vasodilation and inhibition of vasoconstriction is significantly greater than estradiol. Menopause :
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
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

Showing the most recent 10 out of 51 publications