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

36 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
Pages (from-to)181-196
Number of pages16
JournalCell Reports
Volume24
Issue number1
DOIs
StatePublished - Jul 3 2018

Keywords

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

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