Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes

Beibei Xu, Camille Allard, Ana I. Alvarez-Mercado, Taylor Fuselier, Jun Ho Kim, Laurel A. Coons, Sylvia C. Hewitt, Fumihiko Urano, Kenneth S. Korach, Ellis R. Levin, Peter Arvan, Z. Elizabeth Floyd, Franck Mauvais-Jarvis

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)181-196
Number of pages16
JournalCell reports
Volume24
Issue number1
DOIs
StatePublished - Jul 3 2018

Bibliographical 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:
© 2018

Keywords

  • ERAD
  • SERM
  • bazedoxifene
  • beta cell
  • diabetes
  • endoplasmic reticulum stress
  • estrogens
  • islet
  • proinsulin misfolding
  • sex dimorphism

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