Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes.
| Citation | . “Estrogens Promote Misfolded Proinsulin Degradation To Protect Insulin Production And Delay Diabetes.”. Cell Reports, pp. 181-196. |
| Center | University of Michigan |
| Author | 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, Elizabeth Floyd, Franck Mauvais-Jarvis |
| Keywords | ERAD, SERM, bazedoxifene, beta cell, diabetes, endoplasmic reticulum stress, estrogens, islet, proinsulin misfolding, sex dimorphism |
| 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. |
| Year of Publication |
2018
|
| Journal |
Cell reports
|
| Volume |
24
|
| Issue |
1
|
| Number of Pages |
181-196
|
| Date Published |
12/2018
|
| ISSN Number |
2211-1247
|
| DOI |
10.1016/j.celrep.2018.06.019
|
| Alternate Journal |
Cell Rep
|
| PMID |
29972779
|
| PMCID |
PMC6092934
|
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