Helen E Thomas1, Thomas W Kay. 1. St Vincent's Institute of Medical Research, Department of Medicine, University of Melbourne, St Vincent's Hospital, Fitzroy, Melbourne, Victoria, Australia. hthomas@svi.edu.au
Abstract
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.
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.
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