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mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress
Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensitive signaling components control glucose homeostasis and β cell survival under diabetic stress is not well understood. Here, we show that mice lacking the core nutrient-sensitive signal...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496625/ https://www.ncbi.nlm.nih.gov/pubmed/28606928 http://dx.doi.org/10.1083/jcb.201701085 |
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author | Chau, Gia Cac Im, Dong Uk Kang, Tong Mook Bae, Jeong Mo Kim, Won Pyo, Suhkneung Moon, Eun-Yi Um, Sung Hee |
author_facet | Chau, Gia Cac Im, Dong Uk Kang, Tong Mook Bae, Jeong Mo Kim, Won Pyo, Suhkneung Moon, Eun-Yi Um, Sung Hee |
author_sort | Chau, Gia Cac |
collection | PubMed |
description | Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensitive signaling components control glucose homeostasis and β cell survival under diabetic stress is not well understood. Here, we show that mice lacking the core nutrient-sensitive signaling component mammalian target of rapamycin (mTOR) in β cells exhibit reduced β cell mass and smaller islets. mTOR deficiency leads to a severe reduction in β cell survival and increased mitochondrial oxidative stress in chemical-induced diabetes. Mechanistically, we find that mTOR associates with the carbohydrate-response element–binding protein (ChREBP)–Max-like protein complex and inhibits its transcriptional activity, leading to decreased expression of thioredoxin-interacting protein (TXNIP), a potent inducer of β cell death and oxidative stress. Consistent with this, the levels of TXNIP and ChREBP were highly elevated in human diabetic islets and mTOR-deficient mouse islets. Thus, our results suggest that a nutrient-sensitive mTOR-regulated transcriptional network could be a novel target to improve β cell survival and glucose homeostasis in diabetes. |
format | Online Article Text |
id | pubmed-5496625 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-54966252018-01-03 mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress Chau, Gia Cac Im, Dong Uk Kang, Tong Mook Bae, Jeong Mo Kim, Won Pyo, Suhkneung Moon, Eun-Yi Um, Sung Hee J Cell Biol Research Articles Impaired nutrient sensing and dysregulated glucose homeostasis are common in diabetes. However, how nutrient-sensitive signaling components control glucose homeostasis and β cell survival under diabetic stress is not well understood. Here, we show that mice lacking the core nutrient-sensitive signaling component mammalian target of rapamycin (mTOR) in β cells exhibit reduced β cell mass and smaller islets. mTOR deficiency leads to a severe reduction in β cell survival and increased mitochondrial oxidative stress in chemical-induced diabetes. Mechanistically, we find that mTOR associates with the carbohydrate-response element–binding protein (ChREBP)–Max-like protein complex and inhibits its transcriptional activity, leading to decreased expression of thioredoxin-interacting protein (TXNIP), a potent inducer of β cell death and oxidative stress. Consistent with this, the levels of TXNIP and ChREBP were highly elevated in human diabetic islets and mTOR-deficient mouse islets. Thus, our results suggest that a nutrient-sensitive mTOR-regulated transcriptional network could be a novel target to improve β cell survival and glucose homeostasis in diabetes. The Rockefeller University Press 2017-07-03 /pmc/articles/PMC5496625/ /pubmed/28606928 http://dx.doi.org/10.1083/jcb.201701085 Text en © 2017 Chau et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Chau, Gia Cac Im, Dong Uk Kang, Tong Mook Bae, Jeong Mo Kim, Won Pyo, Suhkneung Moon, Eun-Yi Um, Sung Hee mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress |
title | mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress |
title_full | mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress |
title_fullStr | mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress |
title_full_unstemmed | mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress |
title_short | mTOR controls ChREBP transcriptional activity and pancreatic β cell survival under diabetic stress |
title_sort | mtor controls chrebp transcriptional activity and pancreatic β cell survival under diabetic stress |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496625/ https://www.ncbi.nlm.nih.gov/pubmed/28606928 http://dx.doi.org/10.1083/jcb.201701085 |
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