Cargando…
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...
Autores principales: | , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783425864044642304 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6559792 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT janginsook pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT pottekatanita pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT poothongjuthakorn pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT yongjing pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT lagunasacostajacqueline pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT charbonoadriana pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT chenzhouji pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT scheunerdonalynl pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT liuming pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT itkinansaripamela pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT arvanpeter pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity AT kaufmanrandalj pdia1p4hbisrequiredforefficientproinsulinmaturationandßcellhealthinresponsetodietinducedobesity |