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PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity

Regulated proinsulin biosynthesis, disulfide bond formation and ER redox homeostasis are essential to prevent Type two diabetes. In ß cells, protein disulfide isomerase A1 (PDIA1/P4HB), the most abundant ER oxidoreductase of over 17 members, can interact with proinsulin to influence disulfide matura...

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Autores principales: Jang, Insook, Pottekat, Anita, Poothong, Juthakorn, Yong, Jing, Lagunas-Acosta, Jacqueline, Charbono, Adriana, Chen, Zhouji, Scheuner, Donalyn L, Liu, Ming, Itkin-Ansari, Pamela, Arvan, Peter, Kaufman, Randal J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559792/
https://www.ncbi.nlm.nih.gov/pubmed/31184304
http://dx.doi.org/10.7554/eLife.44528
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author Jang, Insook
Pottekat, Anita
Poothong, Juthakorn
Yong, Jing
Lagunas-Acosta, Jacqueline
Charbono, Adriana
Chen, Zhouji
Scheuner, Donalyn L
Liu, Ming
Itkin-Ansari, Pamela
Arvan, Peter
Kaufman, Randal J
author_facet Jang, Insook
Pottekat, Anita
Poothong, Juthakorn
Yong, Jing
Lagunas-Acosta, Jacqueline
Charbono, Adriana
Chen, Zhouji
Scheuner, Donalyn L
Liu, Ming
Itkin-Ansari, Pamela
Arvan, Peter
Kaufman, Randal J
author_sort Jang, Insook
collection PubMed
description Regulated proinsulin biosynthesis, disulfide bond formation and ER redox homeostasis are essential to prevent Type two diabetes. In ß cells, protein disulfide isomerase A1 (PDIA1/P4HB), the most abundant ER oxidoreductase of over 17 members, can interact with proinsulin to influence disulfide maturation. Here we find Pdia1 is required for optimal insulin production under metabolic stress in vivo. ß cell-specific Pdia1 deletion in young high-fat diet fed mice or aged mice exacerbated glucose intolerance with inadequate insulinemia and increased the proinsulin/insulin ratio in both serum and islets compared to wildtype mice. Ultrastructural abnormalities in Pdia1-null ß cells include diminished insulin granule content, ER vesiculation and distention, mitochondrial swelling and nuclear condensation. Furthermore, Pdia1 deletion increased accumulation of disulfide-linked high molecular weight proinsulin complexes and islet vulnerability to oxidative stress. These findings demonstrate that PDIA1 contributes to oxidative maturation of proinsulin in the ER to support insulin production and ß cell health.
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spelling pubmed-65597922019-06-12 PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity Jang, Insook Pottekat, Anita Poothong, Juthakorn Yong, Jing Lagunas-Acosta, Jacqueline Charbono, Adriana Chen, Zhouji Scheuner, Donalyn L Liu, Ming Itkin-Ansari, Pamela Arvan, Peter Kaufman, Randal J eLife Cell Biology Regulated proinsulin biosynthesis, disulfide bond formation and ER redox homeostasis are essential to prevent Type two diabetes. In ß cells, protein disulfide isomerase A1 (PDIA1/P4HB), the most abundant ER oxidoreductase of over 17 members, can interact with proinsulin to influence disulfide maturation. Here we find Pdia1 is required for optimal insulin production under metabolic stress in vivo. ß cell-specific Pdia1 deletion in young high-fat diet fed mice or aged mice exacerbated glucose intolerance with inadequate insulinemia and increased the proinsulin/insulin ratio in both serum and islets compared to wildtype mice. Ultrastructural abnormalities in Pdia1-null ß cells include diminished insulin granule content, ER vesiculation and distention, mitochondrial swelling and nuclear condensation. Furthermore, Pdia1 deletion increased accumulation of disulfide-linked high molecular weight proinsulin complexes and islet vulnerability to oxidative stress. These findings demonstrate that PDIA1 contributes to oxidative maturation of proinsulin in the ER to support insulin production and ß cell health. eLife Sciences Publications, Ltd 2019-06-11 /pmc/articles/PMC6559792/ /pubmed/31184304 http://dx.doi.org/10.7554/eLife.44528 Text en © 2019, Jang et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Jang, Insook
Pottekat, Anita
Poothong, Juthakorn
Yong, Jing
Lagunas-Acosta, Jacqueline
Charbono, Adriana
Chen, Zhouji
Scheuner, Donalyn L
Liu, Ming
Itkin-Ansari, Pamela
Arvan, Peter
Kaufman, Randal J
PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity
title PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity
title_full PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity
title_fullStr PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity
title_full_unstemmed PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity
title_short PDIA1/P4HB is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity
title_sort pdia1/p4hb is required for efficient proinsulin maturation and ß cell health in response to diet induced obesity
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559792/
https://www.ncbi.nlm.nih.gov/pubmed/31184304
http://dx.doi.org/10.7554/eLife.44528
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