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

doi:10.1016/j.celrep.2018.06.019

Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes

Cell Rep. 2018 Jul 3;24(1):181-196. doi: 10.1016/j.celrep.2018.06.019.

Authors

Affiliations

¹ Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA.
² Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System Medical Center, New Orleans, LA 70112, USA.
³ Department of Food Science and Biotechnology, Andong National University, Andong, Gyeongsangbuk-do 36729, South Korea.
⁴ Receptor Biology Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, Durham, NC 27709, USA; Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
⁵ Receptor Biology Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, Durham, NC 27709, USA.
⁶ Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
⁷ Division of Endocrinology, Veterans Affairs Medical Center, Long Beach, CA 90822, USA; Departments of Medicine and Biochemistry, University of California, Irvine, Irvine, CA 92717, USA.
⁸ Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
⁹ Ubiquitin Lab, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70803, USA.
¹⁰ Diabetes Discovery Research and Gender Medicine Laboratory, Department of Medicine, Section of Endocrinology and Metabolism, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA; Southeast Louisiana Veterans Healthcare System Medical Center, New Orleans, LA 70112, USA. Electronic address: fmauvais@tulane.edu.

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.

Keywords: ERAD; SERM; bazedoxifene; beta cell; diabetes; endoplasmic reticulum stress; estrogens; islet; proinsulin misfolding; sex dimorphism.

Published by Elsevier Inc.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Membrane / drug effects
Cell Membrane / metabolism
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Diabetes Mellitus / metabolism*
Diabetes Mellitus / prevention & control
Endoplasmic Reticulum / drug effects
Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum / ultrastructure
Endoplasmic Reticulum Stress / drug effects
Endoplasmic Reticulum-Associated Degradation / drug effects
Estrogen Receptor alpha / metabolism
Estrogens / pharmacology*
Female
Humans
Indoles / pharmacology
Insulin-Secreting Cells / drug effects
Insulin-Secreting Cells / metabolism
Insulin-Secreting Cells / ultrastructure
Male
Mice, Inbred C57BL
Mitochondria / drug effects
Mitochondria / metabolism
Mitochondria / ultrastructure
Proinsulin / biosynthesis*
Protein Folding* / drug effects
Protein Stability / drug effects
Proteolysis* / drug effects
Response Elements / genetics
Ubiquitin-Conjugating Enzymes / metabolism

Substances

Estrogen Receptor alpha
Estrogens
Indoles
Proinsulin
Ubiquitin-Conjugating Enzymes
bazedoxifene

Abstract

Publication types

MeSH terms

Substances

Grants and funding