Bad News for β-Cell Apoptosis

  1. Helen E. Thomas1,2 and
  2. Trevor J. Biden3,4
  1. 1St. Vincent's Institute, Melbourne, Australia;
  2. 2The University of Melbourne Department of Medicine, St. Vincent's Hospital, Melbourne, Australia;
  3. 3Garvan Institute of Medical Research, Sydney, Australia;
  4. 4Faculty of Medicine, St. Vincent's Clinical School, University of New South Wales, Sydney, Australia.
  1. Corresponding author: Trevor Biden, t.biden{at}garvan.org.au.

Although necrosis also plays a role, β-cell death by apoptosis precipitates type 1 diabetes and also contributes to both type 2 diabetes and islet graft failure after transplantation (1). It is therefore surprising that apoptotic pathways, so well explored in other cell types, have barely been characterized in β-cells. A new study in Diabetes now adds to a growing body of work that addresses how proinflammatory cytokines stimulate the intrinsic apoptotic pathway in β-cells (2).

Apoptotic pathways converge on the activation of cysteine proteases of the caspase family (3). The distal point of this cascade, caspase-3, in turn regulates the morphological and other features that characterize apoptosis. Signaling upstream of caspase-3 involves two major arms known as extrinsic and intrinsic pathways. The extrinsic route is triggered by ligands of so-called death receptors, which include Fas and tumor necrosis factor receptor (TNFR). Activation of these receptors facilitates recruitment and cleavage of initiator caspases (such as caspase-8) that act directly on effector caspases such as caspase-3.

In contrast, the intrinsic pathway (also called the mitochondrial or Bcl-2–regulated pathway) is triggered by a loss of mitochondrial outer membrane potential, which facilitates release of cytochrome c from the mitochondrial membrane to seed a signaling complex that activates a different set of initiator caspases, including caspase-9 (4). This mitochondrial pathway can be initiated by multiple stimuli and is subject to a complex hierarchical regulation by members of the Bcl-2 family (5). Notably, the proapoptotic members, Bax and Bak, …

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