Cargando…

Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells

Type 2 diabetes mellitus (T2DM), one of the most common metabolic diseases, is characterized by insulin resistance and inadequate insulin secretion of β cells. Glycogen phosphorylase (GP) is the key enzyme in glycogen breakdown, and contributes to hepatic glucose production during fasting or during...

Descripción completa

Detalles Bibliográficos
Autores principales: Nagy, Lilla, Béke, Ferenc, Juhász, László, Kovács, Tünde, Juhász-Tóth, Éva, Docsa, Tibor, Tóth, Attila, Gergely, Pál, Somsák, László, Bai, Péter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508380/
https://www.ncbi.nlm.nih.gov/pubmed/32960890
http://dx.doi.org/10.1371/journal.pone.0236081
_version_ 1783585408792133632
author Nagy, Lilla
Béke, Ferenc
Juhász, László
Kovács, Tünde
Juhász-Tóth, Éva
Docsa, Tibor
Tóth, Attila
Gergely, Pál
Somsák, László
Bai, Péter
author_facet Nagy, Lilla
Béke, Ferenc
Juhász, László
Kovács, Tünde
Juhász-Tóth, Éva
Docsa, Tibor
Tóth, Attila
Gergely, Pál
Somsák, László
Bai, Péter
author_sort Nagy, Lilla
collection PubMed
description Type 2 diabetes mellitus (T2DM), one of the most common metabolic diseases, is characterized by insulin resistance and inadequate insulin secretion of β cells. Glycogen phosphorylase (GP) is the key enzyme in glycogen breakdown, and contributes to hepatic glucose production during fasting or during insulin resistance. Pharmacological GP inhibitors are potential glucose lowering agents, which may be used in T2DM therapy. A natural product isolated from the cultured broth of the fungal strain No. 138354, called 2,3-bis(4-hydroxycinnamoyloxy)glutaric acid (FR258900), was discovered a decade ago. In vivo studies showed that FR258900 significantly reduced blood glucose levels in diabetic mice. We previously showed that GP inhibitors can potently enhance the function of β cells. The purpose of this study was to assess whether an analogue of FR258900 can influence β cell function. BF142 (Meso-Dimethyl 2,3‐bis[(E)‐3‐(4‐acetoxyphenyl)prop‐2‐enamido]butanedioate) treatment activated the glucose-stimulated insulin secretion pathway, as indicated by enhanced glycolysis, increased mitochondrial oxidation, significantly increased ATP production, and elevated calcium influx in MIN6 cells. Furthermore, BF142 induced mTORC1-specific phosphorylation of S6K, increased levels of PDX1 and insulin protein, and increased insulin secretion. Our data suggest that BF142 can influence β cell function and can support the insulin producing ability of β cells.
format Online
Article
Text
id pubmed-7508380
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-75083802020-10-01 Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells Nagy, Lilla Béke, Ferenc Juhász, László Kovács, Tünde Juhász-Tóth, Éva Docsa, Tibor Tóth, Attila Gergely, Pál Somsák, László Bai, Péter PLoS One Research Article Type 2 diabetes mellitus (T2DM), one of the most common metabolic diseases, is characterized by insulin resistance and inadequate insulin secretion of β cells. Glycogen phosphorylase (GP) is the key enzyme in glycogen breakdown, and contributes to hepatic glucose production during fasting or during insulin resistance. Pharmacological GP inhibitors are potential glucose lowering agents, which may be used in T2DM therapy. A natural product isolated from the cultured broth of the fungal strain No. 138354, called 2,3-bis(4-hydroxycinnamoyloxy)glutaric acid (FR258900), was discovered a decade ago. In vivo studies showed that FR258900 significantly reduced blood glucose levels in diabetic mice. We previously showed that GP inhibitors can potently enhance the function of β cells. The purpose of this study was to assess whether an analogue of FR258900 can influence β cell function. BF142 (Meso-Dimethyl 2,3‐bis[(E)‐3‐(4‐acetoxyphenyl)prop‐2‐enamido]butanedioate) treatment activated the glucose-stimulated insulin secretion pathway, as indicated by enhanced glycolysis, increased mitochondrial oxidation, significantly increased ATP production, and elevated calcium influx in MIN6 cells. Furthermore, BF142 induced mTORC1-specific phosphorylation of S6K, increased levels of PDX1 and insulin protein, and increased insulin secretion. Our data suggest that BF142 can influence β cell function and can support the insulin producing ability of β cells. Public Library of Science 2020-09-22 /pmc/articles/PMC7508380/ /pubmed/32960890 http://dx.doi.org/10.1371/journal.pone.0236081 Text en © 2020 Nagy et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Nagy, Lilla
Béke, Ferenc
Juhász, László
Kovács, Tünde
Juhász-Tóth, Éva
Docsa, Tibor
Tóth, Attila
Gergely, Pál
Somsák, László
Bai, Péter
Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells
title Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells
title_full Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells
title_fullStr Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells
title_full_unstemmed Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells
title_short Glycogen phosphorylase inhibitor, 2,3‐bis[(2E)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (BF142), improves baseline insulin secretion of MIN6 insulinoma cells
title_sort glycogen phosphorylase inhibitor, 2,3‐bis[(2e)‐3‐(4‐hydroxyphenyl)prop‐2‐enamido] butanedioic acid (bf142), improves baseline insulin secretion of min6 insulinoma cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508380/
https://www.ncbi.nlm.nih.gov/pubmed/32960890
http://dx.doi.org/10.1371/journal.pone.0236081
work_keys_str_mv AT nagylilla glycogenphosphorylaseinhibitor23bis2e34hydroxyphenylprop2enamidobutanedioicacidbf142improvesbaselineinsulinsecretionofmin6insulinomacells
AT bekeferenc glycogenphosphorylaseinhibitor23bis2e34hydroxyphenylprop2enamidobutanedioicacidbf142improvesbaselineinsulinsecretionofmin6insulinomacells
AT juhaszlaszlo glycogenphosphorylaseinhibitor23bis2e34hydroxyphenylprop2enamidobutanedioicacidbf142improvesbaselineinsulinsecretionofmin6insulinomacells
AT kovacstunde glycogenphosphorylaseinhibitor23bis2e34hydroxyphenylprop2enamidobutanedioicacidbf142improvesbaselineinsulinsecretionofmin6insulinomacells
AT juhasztotheva glycogenphosphorylaseinhibitor23bis2e34hydroxyphenylprop2enamidobutanedioicacidbf142improvesbaselineinsulinsecretionofmin6insulinomacells
AT docsatibor glycogenphosphorylaseinhibitor23bis2e34hydroxyphenylprop2enamidobutanedioicacidbf142improvesbaselineinsulinsecretionofmin6insulinomacells
AT tothattila glycogenphosphorylaseinhibitor23bis2e34hydroxyphenylprop2enamidobutanedioicacidbf142improvesbaselineinsulinsecretionofmin6insulinomacells
AT gergelypal glycogenphosphorylaseinhibitor23bis2e34hydroxyphenylprop2enamidobutanedioicacidbf142improvesbaselineinsulinsecretionofmin6insulinomacells
AT somsaklaszlo glycogenphosphorylaseinhibitor23bis2e34hydroxyphenylprop2enamidobutanedioicacidbf142improvesbaselineinsulinsecretionofmin6insulinomacells
AT baipeter glycogenphosphorylaseinhibitor23bis2e34hydroxyphenylprop2enamidobutanedioicacidbf142improvesbaselineinsulinsecretionofmin6insulinomacells