JOURNAL OF CELLULAR PHYSIOLOGY 200:177–200 (2004) REVIEW ARTICLE Role of Caspases in the Regulation of Apoptotic Pancreatic Islet Beta-Cells Death HONGXIANG HUI, 1,2 FRANCESCO DOTTA, 3 UMBERTO DI MARIO, 3 AND RICCARDO PERFETTI 1,2 * 1 Division of Diabetes, Endocrinology and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California 2 University of California Los Angeles, Los Angeles, California 3 Department of Clinical Sciences, Endocrinology, University ‘‘La Sapienza’’, Italy The homeostatic control of beta-cell mass in normal and pathological conditions is based on the balance of proliferation, differentiation, and death of the insulin- secreting cells. A considerable body of evidence, accumulated during the last decade, has emphasized the significance of the disregulation of the mechnanisms regulating the apoptosis of beta-cells in the sequence of events that lead to the development of diabetes. The identification of agents capable of interfering with this process needs to be based on a better understanding of the beta-cell specific pathways that are activated during apoptosis. The aim of this article is fivefold: (1) a review of the evidence for beta-cell apoptosis in Type I diabetes, Type II diabetes, and islet transplantation, (2) to review the common stimuli and their mechanisms in pancreatic beta-cell apoptosis, (3) to review the role of caspases and their activation pathway in beta-cell apoptosis, (4) to review the caspase cascade and morphological cellular changes in apoptotic beta-cells, and (5) to highlight the putative strategies for preventing pancreatic beta-cells from apoptosis. J. Cell. Physiol. 200: 177 – 200, 2004. ß 2004 Wiley-Liss, Inc. The growth and development of the endocrine pan- creas has been studied for many years. Questions concerning the regulation of the mass of insulin- producing beta-cells both in the normal growing pan- creas and during the pathogenesis of diabetes have been highlighted in the past several years, especially the relationship between the loss of pancreatic beta-cells and apoptosis. Apoptosis, or programmed cell death (PCD), is an important mechanism for tissue modeling during development and adult life. Cell apoptosis plays an essential role in the removal of superfluous, infected, transformed, or damaged cells by activation of an intrinsic suicide program (Payne et al., 1995; Warner, 1997). In addition, this is also a fundamental mechanism leading to cell loss and disease. Pancreatic beta-cells are sensitive to a number of pro-apoptotic stimuli believed to be involved in the development of Types I and II diabetes (O’Brien et al., 1997; Mathis et al., 2001), as well as in the late complications of diabetes (Darby et al., 1997; Fukagawa et al., 2001). During the last few years, there have been significant advances in our understanding of the pathogenetic mechanisms responsible for the beta-cell loss associated with diabetes and failure of islet transplantation. There is evidence of decreased beta-cell mass in both diabetes and islet transplantation mainly by initiation of the apoptosis process. Therefore, to understand the patho- genesis of diabetes and rationalize its treatment, one must first appreciate the basic events in beta-cell apoptosis. APOPTOSIS IN PANCREATIC BETA-CELLS Type I insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that results from the destruc- tion of insulin-secreting pancreatic islet beta-cells by autoreactive cells and their mediators, such as cytokines (Sjoholm, 1998; Kreuwel and Sherman, 2001). Several recent studies have investigated the role of cell apoptosis in the events leading to the immune-mediated loss of beta-cells either in vitro or ex vivo. Based on studies of pancreatic biopsies taken from diabetes-prone and diabetes-resistant BB/S rats, Lally et al. (2001) show- ed that the appearance of beta-cell apoptosis in the diabetes-prone group was detectable as early as 68 days of life (long before the onset of diabetes). This was followed by an acceleration of apoptosis rate around 85 days of age in the diabetes-prone group, which co- incided with the onset of hyperglycemia. Similarly, Augstein et al. (1998), using NOD (non-obese diabetic) ß 2004 WILEY-LISS, INC. *Correspondence to: Riccardo Perfetti, Division of Endocrinology and Metabolism, Becker Building, Room B-131, Department of Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048. E-mail: perfettir@cshs.org Received 1 October 2003; Accepted 6 November 2004 DOI: 10.1002/jcp.20021