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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Appel, Michael C
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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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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