Desmoglein-2 is important for islet function and β-cell survival
(2022) In Cell Death & Disease 13(10).- 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... (More)
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 (Dsg2lo/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. Dsg2lo/lo mice also exhibited a reduction in blood vessel barrier integrity, an increased incidence of streptozotocin-induced diabetes, and islets isolated from Dsg2lo/lo mice were more susceptible to cytokine-induced β-cell apoptosis. Following transplantation into diabetic mice, islets isolated from Dsg2lo/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.
(Less)
- author
- organization
- publishing date
- 2022-10-29
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Mice, Humans, Animals, Diabetes Mellitus, Type 1/metabolism, Diabetes Mellitus, Experimental/genetics, Streptozocin, Cell Survival, Islets of Langerhans/metabolism, Insulin/metabolism, Desmogleins/metabolism
- in
- Cell Death & Disease
- volume
- 13
- issue
- 10
- article number
- 911
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:36309486
- scopus:85140748098
- ISSN
- 2041-4889
- DOI
- 10.1038/s41419-022-05326-2
- language
- English
- LU publication?
- yes
- additional info
- © 2022. The Author(s).
- id
- 8e2dcd26-f074-472a-8003-895cbbc69dcb
- date added to LUP
- 2022-11-01 20:27:08
- date last changed
- 2024-04-18 17:52:39
@article{8e2dcd26-f074-472a-8003-895cbbc69dcb,
abstract = {{<p>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 (Dsg2lo/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. Dsg2lo/lo mice also exhibited a reduction in blood vessel barrier integrity, an increased incidence of streptozotocin-induced diabetes, and islets isolated from Dsg2lo/lo mice were more susceptible to cytokine-induced β-cell apoptosis. Following transplantation into diabetic mice, islets isolated from Dsg2lo/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.</p>}},
author = {{Myo Min, Kay K and Rojas-Canales, Darling and Penko, Daniella and DeNichilo, Mark and Cockshell, Michaelia P and Ffrench, Charlie B and Thompson, Emma J and Asplund, Olof and Drogemuller, Christopher J and Prasad, Rashmi B and Groop, Leif and Grey, Shane T and Thomas, Helen E and Loudovaris, Thomas and Kay, Thomas W and Mahoney, My G and Jessup, Claire F and Coates, P Toby and Bonder, Claudine S}},
issn = {{2041-4889}},
keywords = {{Mice; Humans; Animals; Diabetes Mellitus, Type 1/metabolism; Diabetes Mellitus, Experimental/genetics; Streptozocin; Cell Survival; Islets of Langerhans/metabolism; Insulin/metabolism; Desmogleins/metabolism}},
language = {{eng}},
month = {{10}},
number = {{10}},
publisher = {{Nature Publishing Group}},
series = {{Cell Death & Disease}},
title = {{Desmoglein-2 is important for islet function and β-cell survival}},
url = {{http://dx.doi.org/10.1038/s41419-022-05326-2}},
doi = {{10.1038/s41419-022-05326-2}},
volume = {{13}},
year = {{2022}},
}