Abstract

Objective. Bcl-xL is an anti-apoptotic member of the Bcl-2 family of proteins and is a potent regulator of cell death. We investigated the importance of Bcl-xL for β cells by deleting the Bcl-x gene specifically in β cells and analyzing their survival in vivo and in culture.

Research Design and Methods. Islets with β cells lacking the Bcl-x gene were assessed in vivo by histology and by treatment of mice with low dose streptozotocin. Islets were isolated by collagenase digestion and treated in culture with the apoptosis inducers staurosporine, thapsigargin, γ-irradiation, pro-inflammatory cytokines or Fas ligand. Cell death was assessed by flow cytometric analysis of sub-genomic DNA.

Results. Bcl-xL deficient β cells developed but were abnormally sensitive to apoptosis induced in vivo by low dose streptozotocin. Although a small proportion of β cells still expressed Bcl-xL, these did not have a survival advantage over their Bcl-xL deficient neighbours. Islets appeared normal after collagenase isolation and whole islet culture. They were, however, abnormally sensitive in culture to a number of different apoptotic stimuli including cytotoxic drugs, proinflammatory cytokines and Fas ligand.

Conclusions. Bcl-xL expression in β cells is dispensible during islet development in the mouse. Bcl-xL is, however, an important regulator of β cell death under conditions of synchronous stress. Bcl-xL expression at physiological levels may partially protect β cells from apoptotic stimuli – including apoptosis due to mediators implicated in type 1 diabetes and death/degeneration of transplanted islets.