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 journalArticle

3 Citations (Scopus)

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

Fingerprint

Conjugated (USP) Estrogens
Proinsulin
Medical problems
Estrogens
Insulin
Degradation
Endoplasmic Reticulum
Type 2 Diabetes Mellitus
Proteolysis
Endoplasmic Reticulum-Associated Degradation
Ubiquitin-Conjugating Enzymes
Endoplasmic Reticulum Stress
Cytoprotection
Nuclear Envelope
Estrogen Receptors
Modulators
Proteins
Chemical activation
Membranes

Keywords

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

Cite this

Xu, B., Allard, C., Alvarez-Mercado, A. I., Fuselier, T., Kim, J. H., Coons, L. A., ... Mauvais-Jarvis, F. (2018). Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes. Cell reports, 24(1), 181-196. https://doi.org/10.1016/j.celrep.2018.06.019

Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes. / Xu, Beibei; Allard, Camille; Alvarez-Mercado, Ana I.; Fuselier, Taylor; Kim, Jun Ho; Coons, Laurel A.; Hewitt, Sylvia C.; Urano, Fumihiko; Korach, Kenneth S.; Levin, Ellis R.; Arvan, Peter; Floyd, Z. Elizabeth; Mauvais-Jarvis, Franck.

In: Cell reports, Vol. 24, No. 1, 03.07.2018, p. 181-196.

Research output: Contribution to journalArticle

Xu, B, Allard, C, Alvarez-Mercado, AI, Fuselier, T, Kim, JH, Coons, LA, Hewitt, SC, Urano, F, Korach, KS, Levin, ER, Arvan, P, Floyd, ZE & Mauvais-Jarvis, F 2018, 'Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes', Cell reports, vol. 24, no. 1, pp. 181-196. https://doi.org/10.1016/j.celrep.2018.06.019
Xu, Beibei ; Allard, Camille ; Alvarez-Mercado, Ana I. ; Fuselier, Taylor ; Kim, Jun Ho ; Coons, Laurel A. ; Hewitt, Sylvia C. ; Urano, Fumihiko ; Korach, Kenneth S. ; Levin, Ellis R. ; Arvan, Peter ; Floyd, Z. Elizabeth ; Mauvais-Jarvis, Franck. / Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes. In: Cell reports. 2018 ; Vol. 24, No. 1. pp. 181-196.
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