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 #
5R01DK074970-04
Application #
7787426
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
2010-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2010
Total Cost
$328,991
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
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
Gautier, Jean-François; 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

Showing the most recent 10 out of 51 publications