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

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

Neurosurgery

Research output: Contribution to journal › Article › peer-review

81 Scopus citations

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.

Original language	English (US)
Pages (from-to)	181-196
Number of pages	16
Journal	Cell reports
Volume	24
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2018.06.019
State	Published - Jul 3 2018

Bibliographical note

Funding Information:
This work was supported by grants from the NIH (DK074970 and DK107444), by a Department of Veterans Affairs Merit Review Award (BX003725), and by an investigator-initiated award from Pfizer (WS2069876) to F.M.-J. and, in part, by a LA CaTS Center grant (1 U54 GM104940). Z.E.F. was supported by an NIH grant (DK099625). P.A. was supported by NIH grant (DK48280), and K.S.K. was supported by the Division of Intramural Research, NIEHS/NIH (1ZIAES70065).

Funding Information:
This work was supported by grants from the NIH ( DK074970 and DK107444 ), by a Department of Veterans Affairs Merit Review Award ( BX003725 ), and by an investigator-initiated award from Pfizer ( WS2069876 ) to F.M.-J. and, in part, by a LA CaTS Center grant ( 1 U54 GM104940 ). Z.E.F. was supported by an NIH grant ( DK099625 ). P.A. was supported by NIH grant ( DK48280 ), and K.S.K. was supported by the Division of Intramural Research, NIEHS/NIH ( 1ZIAES70065 ).

Publisher Copyright:
© 2018

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ERAD
SERM
bazedoxifene
beta cell
diabetes
endoplasmic reticulum stress
estrogens
islet
proinsulin misfolding
sex dimorphism

Publisher link

10.1016/j.celrep.2018.06.019

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092934

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title = "Estrogens Promote Misfolded Proinsulin Degradation to Protect Insulin Production and Delay Diabetes",

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",

author = "Beibei Xu and Camille Allard and Alvarez-Mercado, \{Ana I.\} and Taylor Fuselier and Kim, \{Jun Ho\} and Coons, \{Laurel A.\} and Hewitt, \{Sylvia C.\} and Fumihiko Urano and Korach, \{Kenneth S.\} and Levin, \{Ellis R.\} and Peter Arvan and Floyd, \{Z. Elizabeth\} and Franck Mauvais-Jarvis",

note = "Funding Information: This work was supported by grants from the NIH (DK074970 and DK107444), by a Department of Veterans Affairs Merit Review Award (BX003725), and by an investigator-initiated award from Pfizer (WS2069876) to F.M.-J. and, in part, by a LA CaTS Center grant (1 U54 GM104940). Z.E.F. was supported by an NIH grant (DK099625). P.A. was supported by NIH grant (DK48280), and K.S.K. was supported by the Division of Intramural Research, NIEHS/NIH (1ZIAES70065). Funding Information: This work was supported by grants from the NIH ( DK074970 and DK107444 ), by a Department of Veterans Affairs Merit Review Award ( BX003725 ), and by an investigator-initiated award from Pfizer ( WS2069876 ) to F.M.-J. and, in part, by a LA CaTS Center grant ( 1 U54 GM104940 ). Z.E.F. was supported by an NIH grant ( DK099625 ). P.A. was supported by NIH grant ( DK48280 ), and K.S.K. was supported by the Division of Intramural Research, NIEHS/NIH ( 1ZIAES70065 ). Publisher Copyright: {\textcopyright} 2018",

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AU - Alvarez-Mercado, Ana I.

AU - Fuselier, Taylor

AU - Kim, Jun Ho

AU - Coons, Laurel A.

AU - Hewitt, Sylvia C.

AU - Urano, Fumihiko

AU - Korach, Kenneth S.

AU - Levin, Ellis R.

AU - Arvan, Peter

AU - Floyd, Z. Elizabeth

AU - Mauvais-Jarvis, Franck

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N2 - 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.

AB - 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.

KW - ERAD

KW - SERM

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KW - diabetes

KW - endoplasmic reticulum stress

KW - estrogens

KW - islet

KW - proinsulin misfolding

KW - sex dimorphism

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M3 - Article

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AN - SCOPUS:85048993789

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VL - 24

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JO - Cell reports

JF - Cell reports

IS - 1

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

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