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Nutrient-dependent regulation of β-cell proinsulin content
Insulin is made from proinsulin, but the extent to which fasting/feeding controls the homeostatically regulated proinsulin pool in pancreatic β-cells remains largely unknown. Here, we first examined β-cell lines (INS1E and Min6, which proliferate slowly and are routinely fed fresh medium every 2–3 d...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10302188/ https://www.ncbi.nlm.nih.gov/pubmed/37209827 http://dx.doi.org/10.1016/j.jbc.2023.104836 |
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author | Xu, Xiaoxi Arunagiri, Anoop Alam, Maroof Haataja, Leena Evans, Charles R. Zhao, Ivy Castro-Gutierrez, Roberto Russ, Holger A. Demangel, Caroline Qi, Ling Tsai, Billy Liu, Ming Arvan, Peter |
author_facet | Xu, Xiaoxi Arunagiri, Anoop Alam, Maroof Haataja, Leena Evans, Charles R. Zhao, Ivy Castro-Gutierrez, Roberto Russ, Holger A. Demangel, Caroline Qi, Ling Tsai, Billy Liu, Ming Arvan, Peter |
author_sort | Xu, Xiaoxi |
collection | PubMed |
description | Insulin is made from proinsulin, but the extent to which fasting/feeding controls the homeostatically regulated proinsulin pool in pancreatic β-cells remains largely unknown. Here, we first examined β-cell lines (INS1E and Min6, which proliferate slowly and are routinely fed fresh medium every 2–3 days) and found that the proinsulin pool size responds to each feeding within 1 to 2 h, affected both by the quantity of fresh nutrients and the frequency with which they are provided. We observed no effect of nutrient feeding on the overall rate of proinsulin turnover as quantified from cycloheximide-chase experiments. We show that nutrient feeding is primarily linked to rapid dephosphorylation of translation initiation factor eIF2α, presaging increased proinsulin levels (and thereafter, insulin levels), followed by its rephosphorylation during the ensuing hours that correspond to a fall in proinsulin levels. The decline of proinsulin levels is blunted by the integrated stress response inhibitor, ISRIB, or by inhibition of eIF2α rephosphorylation with a general control nonderepressible 2 (not PERK) kinase inhibitor. In addition, we demonstrate that amino acids contribute importantly to the proinsulin pool; mass spectrometry shows that β-cells avidly consume extracellular glutamine, serine, and cysteine. Finally, we show that in both rodent and human pancreatic islets, fresh nutrient availability dynamically increases preproinsulin, which can be quantified without pulse-labeling. Thus, the proinsulin available for insulin biosynthesis is rhythmically controlled by fasting/feeding cycles. |
format | Online Article Text |
id | pubmed-10302188 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-103021882023-06-29 Nutrient-dependent regulation of β-cell proinsulin content Xu, Xiaoxi Arunagiri, Anoop Alam, Maroof Haataja, Leena Evans, Charles R. Zhao, Ivy Castro-Gutierrez, Roberto Russ, Holger A. Demangel, Caroline Qi, Ling Tsai, Billy Liu, Ming Arvan, Peter J Biol Chem Research Article Insulin is made from proinsulin, but the extent to which fasting/feeding controls the homeostatically regulated proinsulin pool in pancreatic β-cells remains largely unknown. Here, we first examined β-cell lines (INS1E and Min6, which proliferate slowly and are routinely fed fresh medium every 2–3 days) and found that the proinsulin pool size responds to each feeding within 1 to 2 h, affected both by the quantity of fresh nutrients and the frequency with which they are provided. We observed no effect of nutrient feeding on the overall rate of proinsulin turnover as quantified from cycloheximide-chase experiments. We show that nutrient feeding is primarily linked to rapid dephosphorylation of translation initiation factor eIF2α, presaging increased proinsulin levels (and thereafter, insulin levels), followed by its rephosphorylation during the ensuing hours that correspond to a fall in proinsulin levels. The decline of proinsulin levels is blunted by the integrated stress response inhibitor, ISRIB, or by inhibition of eIF2α rephosphorylation with a general control nonderepressible 2 (not PERK) kinase inhibitor. In addition, we demonstrate that amino acids contribute importantly to the proinsulin pool; mass spectrometry shows that β-cells avidly consume extracellular glutamine, serine, and cysteine. Finally, we show that in both rodent and human pancreatic islets, fresh nutrient availability dynamically increases preproinsulin, which can be quantified without pulse-labeling. Thus, the proinsulin available for insulin biosynthesis is rhythmically controlled by fasting/feeding cycles. American Society for Biochemistry and Molecular Biology 2023-05-19 /pmc/articles/PMC10302188/ /pubmed/37209827 http://dx.doi.org/10.1016/j.jbc.2023.104836 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Xu, Xiaoxi Arunagiri, Anoop Alam, Maroof Haataja, Leena Evans, Charles R. Zhao, Ivy Castro-Gutierrez, Roberto Russ, Holger A. Demangel, Caroline Qi, Ling Tsai, Billy Liu, Ming Arvan, Peter Nutrient-dependent regulation of β-cell proinsulin content |
title | Nutrient-dependent regulation of β-cell proinsulin content |
title_full | Nutrient-dependent regulation of β-cell proinsulin content |
title_fullStr | Nutrient-dependent regulation of β-cell proinsulin content |
title_full_unstemmed | Nutrient-dependent regulation of β-cell proinsulin content |
title_short | Nutrient-dependent regulation of β-cell proinsulin content |
title_sort | nutrient-dependent regulation of β-cell proinsulin content |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10302188/ https://www.ncbi.nlm.nih.gov/pubmed/37209827 http://dx.doi.org/10.1016/j.jbc.2023.104836 |
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