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
Affiliations
Beibei Xu
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
Camille Allard
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
Ana I. Alvarez-Mercado
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
Taylor Fuselier
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
Jun Ho Kim
Department of Food Science and Biotechnology, Andong National University, Andong, Gyeongsangbuk-do 36729, South Korea
Laurel A. Coons
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
Sylvia C. Hewitt
Receptor Biology Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, Durham, NC 27709, USA
Fumihiko Urano
Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA
Kenneth S. Korach
Receptor Biology Section, Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, Durham, NC 27709, USA
Ellis R. Levin
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
Peter Arvan
Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, MI 48105, USA
Z. Elizabeth Floyd
Ubiquitin Lab, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70803, USA
Franck Mauvais-Jarvis
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; Corresponding author
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
