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.