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- Title
Desmoglein-2 is important for islet function and β-cell survival.
- Authors
Myo Min, Kay K.; Rojas-Canales, Darling; Penko, Daniella; DeNichilo, Mark; Cockshell, Michaelia P.; Ffrench, Charlie B.; Thompson, Emma J.; Asplund, Olof; Drogemuller, Christopher J.; Prasad, Rashmi B.; Groop, Leif; Grey, Shane T.; Thomas, Helen E.; Loudovaris, Thomas; Kay, Thomas W.; Mahoney, My G.; Jessup, Claire F.; Coates, P. Toby; Bonder, Claudine S.
- 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 (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.
- Publication
Cell Death & Disease, 2022, Vol 13, Issue 10, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-022-05326-2