Differential Effects of <i>Furin</i> Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice
The insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic β cells is...
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/12/6344 |
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| author | Ilaria Coppola Bas Brouwers Sandra Meulemans Bruno Ramos-Molina John W. M. Creemers |
| author_facet | Ilaria Coppola Bas Brouwers Sandra Meulemans Bruno Ramos-Molina John W. M. Creemers |
| author_sort | Ilaria Coppola |
| collection | DOAJ |
| description | The insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic β cells is still controversial. In this study, we investigated the cleavage of the IR by the proprotein convertase FURIN in β cells and hepatocytes, and the contribution of the IR in pancreatic β cells and liver to glucose homeostasis. β-cell-specific <i>Furin</i> knockout (β<i>Fur</i>KO) mice were glucose intolerant, but liver-specific <i>Furin</i> knockout (L<i>Fur</i>KO) mice were normoglycemic. Processing of the IR was blocked in β<i>Fur</i>KO cells, but unaffected in L<i>Fur</i>KO mice. Most strikingly, glucose homeostasis in β-cell-specific IR knockout (βIRKO) mice was normal in younger mice (up to 20 weeks), and only mildly affected in older mice (24 weeks). In conclusion, FURIN cleaves the IR non-redundantly in β cells, but redundantly in liver. Furthermore, we demonstrated that the IR in β cells plays a limited role in glucose homeostasis. |
| first_indexed | 2024-03-10T10:26:32Z |
| format | Article |
| id | doaj.art-a21327403eb3498d99a18db490f4b697 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:26:32Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a21327403eb3498d99a18db490f4b6972023-11-22T00:00:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012212634410.3390/ijms22126344Differential Effects of <i>Furin</i> Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of MiceIlaria Coppola0Bas Brouwers1Sandra Meulemans2Bruno Ramos-Molina3John W. M. Creemers4Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, 3000 Leuven, BelgiumLaboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, 3000 Leuven, BelgiumLaboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, 3000 Leuven, BelgiumLaboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, 3000 Leuven, BelgiumLaboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, 3000 Leuven, BelgiumThe insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic β cells is still controversial. In this study, we investigated the cleavage of the IR by the proprotein convertase FURIN in β cells and hepatocytes, and the contribution of the IR in pancreatic β cells and liver to glucose homeostasis. β-cell-specific <i>Furin</i> knockout (β<i>Fur</i>KO) mice were glucose intolerant, but liver-specific <i>Furin</i> knockout (L<i>Fur</i>KO) mice were normoglycemic. Processing of the IR was blocked in β<i>Fur</i>KO cells, but unaffected in L<i>Fur</i>KO mice. Most strikingly, glucose homeostasis in β-cell-specific IR knockout (βIRKO) mice was normal in younger mice (up to 20 weeks), and only mildly affected in older mice (24 weeks). In conclusion, FURIN cleaves the IR non-redundantly in β cells, but redundantly in liver. Furthermore, we demonstrated that the IR in β cells plays a limited role in glucose homeostasis.https://www.mdpi.com/1422-0067/22/12/6344insulin receptorproprotein convertaseFURINliverpancreatic β cellsinsulin signaling |
| spellingShingle | Ilaria Coppola Bas Brouwers Sandra Meulemans Bruno Ramos-Molina John W. M. Creemers Differential Effects of <i>Furin</i> Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice International Journal of Molecular Sciences insulin receptor proprotein convertase FURIN liver pancreatic β cells insulin signaling |
| title | Differential Effects of <i>Furin</i> Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice |
| title_full | Differential Effects of <i>Furin</i> Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice |
| title_fullStr | Differential Effects of <i>Furin</i> Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice |
| title_full_unstemmed | Differential Effects of <i>Furin</i> Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice |
| title_short | Differential Effects of <i>Furin</i> Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice |
| title_sort | differential effects of i furin i deficiency on insulin receptor processing and glucose control in liver and pancreatic β cells of mice |
| topic | insulin receptor proprotein convertase FURIN liver pancreatic β cells insulin signaling |
| url | https://www.mdpi.com/1422-0067/22/12/6344 |
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