Desmoglein-2 is important for islet function and β-cell survival
Abstract Type 1 diabetes is a complex disease characterized by the lack of endogenous insulin secreted from the pancreatic β-cells. Although β-cell targeted autoimmune processes and β-cell dysfunction are known to occur in type 1 diabetes, a complete understanding of the cell-to-cell interactions th...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05326-2 |
| _version_ | 1828316720974004224 |
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| author | Kay K. Myo Min Darling Rojas-Canales Daniella Penko Mark DeNichilo Michaelia P. Cockshell Charlie B. Ffrench Emma J. Thompson Olof Asplund Christopher J. Drogemuller Rashmi B. Prasad Leif Groop Shane T. Grey Helen E. Thomas Thomas Loudovaris Thomas W. Kay My G. Mahoney Claire F. Jessup P. Toby Coates Claudine S. Bonder |
| author_facet | Kay K. Myo Min Darling Rojas-Canales Daniella Penko Mark DeNichilo Michaelia P. Cockshell Charlie B. Ffrench Emma J. Thompson Olof Asplund Christopher J. Drogemuller Rashmi B. Prasad Leif Groop Shane T. Grey Helen E. Thomas Thomas Loudovaris Thomas W. Kay My G. Mahoney Claire F. Jessup P. Toby Coates Claudine S. Bonder |
| author_sort | Kay K. Myo Min |
| collection | DOAJ |
| description | Abstract Type 1 diabetes is a complex disease characterized by the lack of endogenous insulin secreted from the pancreatic β-cells. Although β-cell targeted autoimmune processes and β-cell dysfunction are known to occur in type 1 diabetes, a complete understanding of the cell-to-cell interactions that support pancreatic function is still lacking. To characterize the pancreatic endocrine compartment, we studied pancreata from healthy adult donors and investigated a single cell surface adhesion molecule, desmoglein-2 (DSG2). Genetically-modified mice lacking Dsg2 were examined for islet cell mass, insulin production, responses to glucose, susceptibility to a streptozotocin-induced mouse model of hyperglycaemia, and ability to cure diabetes in a syngeneic transplantation model. Herein, we have identified DSG2 as a previously unrecognized adhesion molecule that supports β-cells. Furthermore, we reveal that DSG2 is within the top 10 percent of all genes expressed by human pancreatic islets and is expressed by the insulin-producing β-cells but not the somatostatin-producing δ-cells. In a Dsg2 loss-of-function mice (Dsg2 lo/lo), we observed a significant reduction in the number of pancreatic islets and islet size, and consequently, there was less total insulin content per islet cluster. Dsg2 lo/lo mice also exhibited a reduction in blood vessel barrier integrity, an increased incidence of streptozotocin-induced diabetes, and islets isolated from Dsg2 lo/lo mice were more susceptible to cytokine-induced β-cell apoptosis. Following transplantation into diabetic mice, islets isolated from Dsg2 lo/lo mice were less effective than their wildtype counterparts at curing diabetes. In vitro assays using the Beta-TC-6 murine β-cell line suggest that DSG2 supports the actin cytoskeleton as well as the release of cytokines and chemokines. Taken together, our study suggests that DSG2 is an under-appreciated regulator of β-cell function in pancreatic islets and that a better understanding of this adhesion molecule may provide new opportunities to combat type 1 diabetes. |
| first_indexed | 2024-04-13T17:18:51Z |
| format | Article |
| id | doaj.art-afcc41530a1443548bde1470cff8d8ab |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T17:18:51Z |
| publishDate | 2022-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-afcc41530a1443548bde1470cff8d8ab2022-12-22T02:38:04ZengNature Publishing GroupCell Death and Disease2041-48892022-10-01131011510.1038/s41419-022-05326-2Desmoglein-2 is important for islet function and β-cell survivalKay K. Myo Min0Darling Rojas-Canales1Daniella Penko2Mark DeNichilo3Michaelia P. Cockshell4Charlie B. Ffrench5Emma J. Thompson6Olof Asplund7Christopher J. Drogemuller8Rashmi B. Prasad9Leif Groop10Shane T. Grey11Helen E. Thomas12Thomas Loudovaris13Thomas W. Kay14My G. Mahoney15Claire F. Jessup16P. Toby Coates17Claudine S. Bonder18Centre for Cancer Biology, University of South Australia and SA PathologyFlinders Renal Laboratory, Renal Unit, Division of Medicine and Critical Care, Southern Adelaide Local Health Network, Flinders Medical CentreAdelaide Medical School, University of AdelaideCentre for Cancer Biology, University of South Australia and SA PathologyCentre for Cancer Biology, University of South Australia and SA PathologyCentre for Cancer Biology, University of South Australia and SA PathologyCentre for Cancer Biology, University of South Australia and SA PathologyGenomics, Diabetes and Endocrinology, Department of Clinical Sciences, Lund UniversityAdelaide Medical School, University of AdelaideGenomics, Diabetes and Endocrinology, Department of Clinical Sciences, Lund UniversityGenomics, Diabetes and Endocrinology, Department of Clinical Sciences, Lund UniversityImmunology Department, Garvan Institute of Medical ResearchSt Vincent’s Institute of Medical Research & the University of MelbourneSt Vincent’s Institute of Medical Research & the University of MelbourneSt Vincent’s Institute of Medical Research & the University of MelbourneDepartment of Dermatology and Cutaneous Biology, Thomas Jefferson UniversityAdelaide Medical School, University of AdelaideAdelaide Medical School, University of AdelaideCentre for Cancer Biology, University of South Australia and SA PathologyAbstract Type 1 diabetes is a complex disease characterized by the lack of endogenous insulin secreted from the pancreatic β-cells. Although β-cell targeted autoimmune processes and β-cell dysfunction are known to occur in type 1 diabetes, a complete understanding of the cell-to-cell interactions that support pancreatic function is still lacking. To characterize the pancreatic endocrine compartment, we studied pancreata from healthy adult donors and investigated a single cell surface adhesion molecule, desmoglein-2 (DSG2). Genetically-modified mice lacking Dsg2 were examined for islet cell mass, insulin production, responses to glucose, susceptibility to a streptozotocin-induced mouse model of hyperglycaemia, and ability to cure diabetes in a syngeneic transplantation model. Herein, we have identified DSG2 as a previously unrecognized adhesion molecule that supports β-cells. Furthermore, we reveal that DSG2 is within the top 10 percent of all genes expressed by human pancreatic islets and is expressed by the insulin-producing β-cells but not the somatostatin-producing δ-cells. In a Dsg2 loss-of-function mice (Dsg2 lo/lo), we observed a significant reduction in the number of pancreatic islets and islet size, and consequently, there was less total insulin content per islet cluster. Dsg2 lo/lo mice also exhibited a reduction in blood vessel barrier integrity, an increased incidence of streptozotocin-induced diabetes, and islets isolated from Dsg2 lo/lo mice were more susceptible to cytokine-induced β-cell apoptosis. Following transplantation into diabetic mice, islets isolated from Dsg2 lo/lo mice were less effective than their wildtype counterparts at curing diabetes. In vitro assays using the Beta-TC-6 murine β-cell line suggest that DSG2 supports the actin cytoskeleton as well as the release of cytokines and chemokines. Taken together, our study suggests that DSG2 is an under-appreciated regulator of β-cell function in pancreatic islets and that a better understanding of this adhesion molecule may provide new opportunities to combat type 1 diabetes.https://doi.org/10.1038/s41419-022-05326-2 |
| spellingShingle | Kay K. Myo Min Darling Rojas-Canales Daniella Penko Mark DeNichilo Michaelia P. Cockshell Charlie B. Ffrench Emma J. Thompson Olof Asplund Christopher J. Drogemuller Rashmi B. Prasad Leif Groop Shane T. Grey Helen E. Thomas Thomas Loudovaris Thomas W. Kay My G. Mahoney Claire F. Jessup P. Toby Coates Claudine S. Bonder Desmoglein-2 is important for islet function and β-cell survival Cell Death and Disease |
| title | Desmoglein-2 is important for islet function and β-cell survival |
| title_full | Desmoglein-2 is important for islet function and β-cell survival |
| title_fullStr | Desmoglein-2 is important for islet function and β-cell survival |
| title_full_unstemmed | Desmoglein-2 is important for islet function and β-cell survival |
| title_short | Desmoglein-2 is important for islet function and β-cell survival |
| title_sort | desmoglein 2 is important for islet function and β cell survival |
| url | https://doi.org/10.1038/s41419-022-05326-2 |
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