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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2023
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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.
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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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