Stressed β-cells contribute to loss of peri-islet extracellular matrix in type 1 diabetes

Abstract

Type 1 diabetes (T1D) is characterized by the immune-mediated destruction of insulin-producing {beta}-cells in pancreatic islets. The peri-islet extracellular matrix (ECM) is a complex protein barrier that is lost in T1D, in part due to infiltrating immune cells. The contribution of stressed {beta}-cells to ECM degradation during T1D remains unclear. To bridge this gap, we used 12-15-week-old NOD mice and pancreas sections from healthy, [≥]2 autoantibody positive (Aab+), and recent onset T1D donors. We focused on MMP-3 due to its role in degrading type IV collagen (COL IV) in the peri-islet ECM. Treatment with proinflammatory cytokines or hyperglycemia increased MMP-3 gene expression and protein levels in mouse and human islets. In NOD pancreas sections, increased MMP-3 expression in {beta}-cells correlates with loss of COL IV during insulitis and hyperglycemia; however, this was independent of insulitis score. We observed similar increases in MMP-3 and loss of COL IV in islets and exocrine tissue from Aab+ and recent onset T1D donors. These results suggest that stressed {beta}-cells degrade the ECM during preclinical T1D, further weakening the peri-islet ECM barrier and facilitating islet infiltration and death. Inhibiting expression of MMP-3 may represent a novel treatment to prevent islet death in T1D.