Intracellular pathways of pancreatic β-cell apoptosis in type 1 diabetes.

Background: Apoptosis of β cells is a feature of type 1 diabetes. It is also increasingly recognized in type 2 diabetes and islet graft rejection.

Methods: We have studied the intracellular pathways that regulate β-cell apoptosis in type 1 and 2 diabetes. We have examined the role of Bid, a pro-apoptotic member of the Bcl-2 family, using islets from mice deficient in Bid. We also studied the Bcl-2 family molecules involved in killing by using high concentrations of reducing sugars such as glucose or ribose.

Results: We found that Bid-deficient islets are protected from recombinant human perforin and granzyme B, as well as from Fas-mediated killing. This makes Bid a target for protection of β cells from multiple insults relevant to type 1 diabetes. In contrast to granzyme B and death receptor signalling, we found that islets lacking Bim or Puma were protected from glucose toxicity.

Conclusions: Our data indicate that different stimuli activate different initiator molecules in the Bcl-2-regulated pathway in β cells.