Cell Reports (Jul 2018)

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

Journal volume & issue
Vol. 24, no. 1
pp. 181 – 196

Abstract

Read online

Summary: 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. : Estrogens prevent diabetes in women, but the mechanism is poorly understood. Xu et al. report that estrogens activate the endoplasmic-reticulum-associated protein degradation pathway, which promotes misfolded proinsulin degradation, suppresses endoplasmic reticulum stress, and protects insulin secretion in mice and in human pancreatic β cells. Keywords: estrogens, beta cell, islet, endoplasmic reticulum stress, proinsulin misfolding, diabetes, bazedoxifene, sex dimorphism, ERAD, SERM