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
Song, Jingwen; Yang, Yunzhong; Mauvais-Jarvis, Franck et al. (2017) KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment. BMC Med Genet 18:64
Xu, Beibei; Lovre, Dragana; Mauvais-Jarvis, Franck (2017) The effect of selective estrogen receptor modulators on type 2 diabetes onset in women: Basic and clinical insights. J Diabetes Complications 31:773-779
Mauvais-Jarvis, Franck (2017) Gender differences in glucose homeostasis and diabetes. Physiol Behav :
Mauvais-Jarvis, Franck; Arnold, Arthur P; Reue, Karen (2017) A Guide for the Design of Pre-clinical Studies on Sex Differences in Metabolism. Cell Metab 25:1216-1230
Xu, Weiwei; Niu, Tianhua; Xu, Beibei et al. (2017) Androgen receptor-deficient islet ?-cells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse. J Diabetes Complications 31:787-795
Mauvais-Jarvis, Franck (2017) New Insights Into Estrogens Inactivation and Prevention of Systemic Inflammation in Male Subjects. Endocrinology 158:3711-3712
Mauvais-Jarvis, Franck; Manson, JoAnn E; Stevenson, John C et al. (2017) Menopausal Hormone Therapy and Type 2 Diabetes Prevention: Evidence, Mechanisms, and Clinical Implications. Endocr Rev 38:173-188
Dong, Shengli; Baranwal, Somesh; Garcia, Anapatricia et al. (2017) Nischarin inhibition alters energy metabolism by activating AMP-activated protein kinase. J Biol Chem 292:16833-16846
Morford, Jamie J; Wu, Sheng; Mauvais-Jarvis, Franck (2017) The impact of androgen actions in neurons on metabolic health and disease. Mol Cell Endocrinol :
Mauvais-Jarvis, Franck (2016) Role of Sex Steroids in ? Cell Function, Growth, and Survival. Trends Endocrinol Metab 27:844-855

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