@article{53c2f7b6b8fc4dfc9039283a43b951f5,
title = "Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes",
abstract = "Conjugated estrogens (CE) delay the onset of type 2 diabetes (T2D) in postmenopausal women, but the mechanism is unclear. In T2D, the endoplasmic reticulum (ER) fails to promote proinsulin folding and, in failing to do so, promotes ER stress and β cell dysfunction. We show that CE prevent insulin-deficient diabetes in male and in female Akita mice using a model of misfolded proinsulin. CE stabilize the ER-associated protein degradation (ERAD) system and promote misfolded proinsulin proteasomal degradation. This involves activation of nuclear and membrane estrogen receptor-α (ERα), promoting transcriptional repression and proteasomal degradation of the ubiquitin-conjugating enzyme and ERAD degrader, UBC6e. The selective ERα modulator bazedoxifene mimics CE protection of β cells in females but not in males.",
keywords = "ERAD, SERM, bazedoxifene, beta cell, diabetes, endoplasmic reticulum stress, estrogens, islet, proinsulin misfolding, sex dimorphism",
author = "Beibei Xu and Camille Allard and Alvarez-Mercado, {Ana I.} and Taylor Fuselier and Kim, {Jun Ho} and Coons, {Laurel A.} and Hewitt, {Sylvia C.} and Fumihiko Urano and Korach, {Kenneth S.} and Levin, {Ellis R.} and Peter Arvan and Floyd, {Z. Elizabeth} and Franck Mauvais-Jarvis",
note = "Funding Information: This work was supported by grants from the NIH (DK074970 and DK107444), by a Department of Veterans Affairs Merit Review Award (BX003725), and by an investigator-initiated award from Pfizer (WS2069876) to F.M.-J. and, in part, by a LA CaTS Center grant (1 U54 GM104940). Z.E.F. was supported by an NIH grant (DK099625). P.A. was supported by NIH grant (DK48280), and K.S.K. was supported by the Division of Intramural Research, NIEHS/NIH (1ZIAES70065). Funding Information: This work was supported by grants from the NIH ( DK074970 and DK107444 ), by a Department of Veterans Affairs Merit Review Award ( BX003725 ), and by an investigator-initiated award from Pfizer ( WS2069876 ) to F.M.-J. and, in part, by a LA CaTS Center grant ( 1 U54 GM104940 ). Z.E.F. was supported by an NIH grant ( DK099625 ). P.A. was supported by NIH grant ( DK48280 ), and K.S.K. was supported by the Division of Intramural Research, NIEHS/NIH ( 1ZIAES70065 ). Publisher Copyright: {\textcopyright} 2018",
year = "2018",
month = jul,
day = "3",
doi = "10.1016/j.celrep.2018.06.019",
language = "English",
volume = "24",
pages = "181--196",
journal = "Cell Reports",
issn = "2211-1247",
number = "1",
}