| First Author | Xu B | Year | 2018 |
| Journal | Cell Rep | Volume | 24 |
| Issue | 1 | Pages | 181-196 |
| PubMed ID | 29972779 | Mgi Jnum | J:270881 |
| Mgi Id | MGI:6278332 | Doi | 10.1016/j.celrep.2018.06.019 |
| Citation | Xu B, et al. (2018) Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes. Cell Rep 24(1):181-196 |
| abstractText | 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 beta 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-alpha (ERalpha), promoting transcriptional repression and proteasomal degradation of the ubiquitin-conjugating enzyme and ERAD degrader, UBC6e. The selective ERalpha modulator bazedoxifene mimics CE protection of beta cells in females but not in males. |
