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
Cell Reports. 2018-07-01; 24(1): 181-196
DOI: 10.1016/j.celrep.2018.06.019


Lire sur PubMed

---

Comment in
Nature. 2018 Jul;559(7713):155.

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.

Auteurs Bordeaux Neurocampus