Dual Trade of Bcl-2 and Bcl-x_L in Islet Physiology

Balancing Life and Death With Metabolism Secretion Coupling

Apoptosis is now recognized as a predominant mechanism by which β cells are destroyed in both type 1 and type 2 diabetes (1). Pro- and antiapoptotic members of the Bcl-2 family are central regulators involved in β-cell fate decision between life and death in response to physiological insults. The intricate interplay and balance between members of this family regulate apoptosis by controlling mitochondrial cell death signaling, the so-called intrinsic pathway (2). The Bcl-2 family is divided into three subgroups as follows: 1) the antiapoptotic Bcl-2–like proteins (Bcl-2, Bcl-x_L, Bcl-W, Mcl-1, and A1/Bfl1) that possess four independent and highly conserved Bcl-2 homology (BH) domains (BH-1 to -4); 2) the proapoptotic Bax-like proteins (Bax, Bak, and Bok/Mtd), which also harbor the four BH domains; and 3) proapoptotic members typified by a single BH-3 domain (Bid, Bim/Bod, Bad, Bmf, Bik/Nbk, Blk, NoxA, Puma/Bbc3, and Hrk/DP5). Members of this last subgroup initiate the apoptotic-signaling cascade by interacting with antiapoptotic members (3). In addition, intracellular calcium activity ([Ca²⁺]_i) is an important second messenger that initiates the apoptotic program (4) as well as being essential in metabolism secretion coupling that drives the Ca²⁺ sensor of the exocytotic machinery (5). Given the importance of Bcl-2 and Bcl-x_L as prosurvival sentinels of the mitochondria, combined with the indispensable function of this organelle in β-cell metabolism secretion coupling, these proteins have been the targets of numerous studies in which expression levels were manipulated with the goal of improving islet viability. The study by Zhou et al. (6) in 2000 was the first to provide proof of concept that overexpression of Bcl-x_L in β cells blunted stressed-induced apoptosis. Unexpectedly, one of the transgenic lines expressing high levels of Bcl-x_L also displayed severe hyperglycemia. Glucose intolerance in these animals was linked to …