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Cell Death Differ. 2010 Apr;17(4):577-85. doi: 10.1038/cdd.2009.165. Epub 2009 Nov 20.

The role of perforin and granzymes in diabetes.

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Department of Immunology and Diabetes, St Vincent's Institute, 41 Victoria Parade, Fitzroy, Melbourne 3065, Australia.


Type 1 diabetes results from autoimmune destruction of pancreatic beta-cells by CD8(+) T cells. The requirement for CD8(+) T cells implicates perforin and granzymes as effectors of tissue destruction. Diabetogenic cytotoxic T cells kill beta-cells by the perforin/granzyme pathway in vitro. In the non-obese diabetic mouse model of type I diabetes, perforin deficiency results in a highly significant reduction in disease, indicating a direct role for perforin in beta-cell death in vivo, although other cell death pathways must account for the residual diabetes in perforin-deficient mice. Perforin and granzyme B are also important in allogeneic destruction of islets. The dominant role of the perforin/granzyme pathway in beta-cell destruction in type I diabetes and allogeneic islet graft rejection make this pathway an important target for blockade in future therapies for type I diabetes. In addition, granzymes have a newly recognized role in inflammation, a feature of both type I and II diabetes, suggesting their role should be further explored in both the common forms of diabetes.

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