Loss of ZNF148 enhances insulin secretion in human pancreatic β cells
Insulin secretion from pancreatic β cells is essential to the maintenance of glucose homeostasis. Defects in this process result in diabetes. Identifying genetic regulators that impair insulin secretion is crucial for the identification of novel therapeutic targets. Here, we show that reduction of Z...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2023-06-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.157572 |
| _version_ | 1827767974890569728 |
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| author | Eleonora de Klerk Yini Xiao Christopher H. Emfinger Mark P. Keller David I. Berrios Valentina Loconte Axel A. Ekman Kate L. White Rebecca L. Cardone Richard G. Kibbey Alan D. Attie Matthias Hebrok |
| author_facet | Eleonora de Klerk Yini Xiao Christopher H. Emfinger Mark P. Keller David I. Berrios Valentina Loconte Axel A. Ekman Kate L. White Rebecca L. Cardone Richard G. Kibbey Alan D. Attie Matthias Hebrok |
| author_sort | Eleonora de Klerk |
| collection | DOAJ |
| description | Insulin secretion from pancreatic β cells is essential to the maintenance of glucose homeostasis. Defects in this process result in diabetes. Identifying genetic regulators that impair insulin secretion is crucial for the identification of novel therapeutic targets. Here, we show that reduction of ZNF148 in human islets, and its deletion in stem cell–derived β cells (SC–β cells), enhances insulin secretion. Transcriptomics of ZNF148-deficient SC–β cells identifies increased expression of annexin and S100 genes whose proteins form tetrameric complexes involved in regulation of insulin vesicle trafficking and exocytosis. ZNF148 in SC–β cells prevents translocation of annexin A2 from the nucleus to its functional place at the cell membrane via direct repression of S100A16 expression. These findings point to ZNF148 as a regulator of annexin-S100 complexes in human β cells and suggest that suppression of ZNF148 may provide a novel therapeutic strategy to enhance insulin secretion. |
| first_indexed | 2024-03-11T12:05:57Z |
| format | Article |
| id | doaj.art-b4b5dbeb38934b90baccd9d13f8ca114 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:05:57Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-b4b5dbeb38934b90baccd9d13f8ca1142023-11-07T16:25:42ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-06-01811Loss of ZNF148 enhances insulin secretion in human pancreatic β cellsEleonora de KlerkYini XiaoChristopher H. EmfingerMark P. KellerDavid I. BerriosValentina LoconteAxel A. EkmanKate L. WhiteRebecca L. CardoneRichard G. KibbeyAlan D. AttieMatthias HebrokInsulin secretion from pancreatic β cells is essential to the maintenance of glucose homeostasis. Defects in this process result in diabetes. Identifying genetic regulators that impair insulin secretion is crucial for the identification of novel therapeutic targets. Here, we show that reduction of ZNF148 in human islets, and its deletion in stem cell–derived β cells (SC–β cells), enhances insulin secretion. Transcriptomics of ZNF148-deficient SC–β cells identifies increased expression of annexin and S100 genes whose proteins form tetrameric complexes involved in regulation of insulin vesicle trafficking and exocytosis. ZNF148 in SC–β cells prevents translocation of annexin A2 from the nucleus to its functional place at the cell membrane via direct repression of S100A16 expression. These findings point to ZNF148 as a regulator of annexin-S100 complexes in human β cells and suggest that suppression of ZNF148 may provide a novel therapeutic strategy to enhance insulin secretion.https://doi.org/10.1172/jci.insight.157572MetabolismStem cells |
| spellingShingle | Eleonora de Klerk Yini Xiao Christopher H. Emfinger Mark P. Keller David I. Berrios Valentina Loconte Axel A. Ekman Kate L. White Rebecca L. Cardone Richard G. Kibbey Alan D. Attie Matthias Hebrok Loss of ZNF148 enhances insulin secretion in human pancreatic β cells JCI Insight Metabolism Stem cells |
| title | Loss of ZNF148 enhances insulin secretion in human pancreatic β cells |
| title_full | Loss of ZNF148 enhances insulin secretion in human pancreatic β cells |
| title_fullStr | Loss of ZNF148 enhances insulin secretion in human pancreatic β cells |
| title_full_unstemmed | Loss of ZNF148 enhances insulin secretion in human pancreatic β cells |
| title_short | Loss of ZNF148 enhances insulin secretion in human pancreatic β cells |
| title_sort | loss of znf148 enhances insulin secretion in human pancreatic β cells |
| topic | Metabolism Stem cells |
| url | https://doi.org/10.1172/jci.insight.157572 |
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