Abstract

OBJECTIVE Bcl-xL is an antiapoptotic member of the Bcl-2 family of proteins and 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 (STZ). Islets were isolated by collagenase digestion and treated in culture with the apoptosis inducers staurosporine, thapsigargin, γ-irradiation, proinflammatory cytokines, or Fas ligand. Cell death was assessed by flow cytometric analysis of subgenomic DNA.

RESULTS Bcl-xL–deficient β-cells developed but were abnormally sensitive to apoptosis induced in vivo by low-dose STZ. Although a small proportion of β-cells still expressed Bcl-xL, these did not have a survival advantage over their Bcl-xL–deficient neighbors. 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 because of mediators implicated in type 1 diabetes and death or degeneration of transplanted islets.