beta-cell apoptosis: stimuli and signaling.

Abstract

Pancreatic ␤-cells are sensitive to a number of proapoptotic stimuli. Thus, apoptosis is an important part of the physiological neonatal remodeling of the endocrine pancreas, and a number of pathological stimuli involved in type 1 and type 2 diabetes have been shown to elicit ␤-cell apoptosis. Factors of relevance to type 1 diabetes include proinflammatory cytokines, nitric oxide, and reactive oxygen species as well as Fas ligand. Recent findings that free fatty acids, glucose, sulfonylurea, and amylin cause ␤-cell apoptosis in vitro suggest that programmed cell death may also be involved in the pathogenesis of type 2 diabetes. Furthermore, there is evidence favoring a convergence in signaling pathways toward common effectors of ␤-cell apoptosis elicited by stimuli implicated in the pathogenesis of type 1 and type 2 diabetes. Therefore, recent studies involving the stimuli and signaling pathways of ␤-cell apoptosis-in particular, mitogen-and stressactivated protein kinases-will be reviewed. It is concluded that immunological, inflammatory, and metabolic signals cause ␤-cell apoptosis, and the possibility that these signals converge toward a common ␤-cell death signaling pathway should be investigated further. Diabetes 50 (Suppl. 1):S58-S63, 2001 G iven the vital necessity of insulin, but also the hazards of release in excess of needs, ␤-cell function and ␤-cell mass are tightly regulated. This evolutionary pressure has resulted in a highly specialized cell that is receptive to replicatory but also apoptotic stimuli to fulfill the need for dynamic regulation. Apoptosis, or programmed cell death, is a physiological mode of remodeling tissue during organogenesis but is also involved in physiology later in life, for example, in relation to thymic involution. It has become clear that the endocrine pancreas is actively remodeled postpartum and that apoptosis is an important mechanism for this (1).Apoptotic cell death is an energy-requiring process that involves de novo protein synthesis. The process is characterized by morphological changes including condensation of nuclear chromatin, cellular shrinkage, membrane blebbing, and the formation of apoptotic bodies that are membrane-surrounded cellular constituents and undergo phagocytosis before leakage of intracellular contents, thereby avoiding the stimulation of an immune response, hence an autoimmune reaction.In many chronic degenerative diseases, apoptosis leads to inappropriate deletion of cells. The apoptotic cascade may be elicited by a number of varying stimuli, including intracellular events, such as metabolic imbalance, cell cycle perturbation, or DNA damage, and extracellular factors, such as activation of death receptors (Fas and tumor necrosis factor [TNF] receptors) and withdrawal of growth factors, metabolic factors, certain hormones, and inflammatory mediators such as cytokines. Intracellular signals involve ceramide; increases in intracellular calcium; free oxygen and nitric oxide (NO) radicals; and protein kinases such as mitogen-activated protein kinas...

Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist

“…As demonstrated in several studies (52)(53)(54), the supply of oxygen in both the early posttransplant period and long-term is largely limited at the intraportal transplantation site, but is nevertheless crucial for islet survival and function. Islets exposed to chronic hypoxia are especially susceptible to hypoxia-mediated inflammatory reactions, oxidative stress, and apoptosis.…”

Continuous stimulation of human glucagon-like peptide-1 (7–36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes

“…Apart from direct killing of beta cells by autoreactive T cells, another possible mechanism of beta cell loss in autoimmune type 1 diabetes may be cytokine-induced apoptosis [33,34]. Recently, it was reported that GLP-1 and other growth factors have an anti-apoptotic effect [11][12][13]35].…”

Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes

“…To distinguish between these two possibilities, we first investigated whether UCP2 deficiency in islets may affect cytokine-induced ␤-cell death, the major death signal for ␤-cells (14,15). A mechanism by which cytokines impair ␤-cell function and, in part, mediate ␤-cell death is by induction of the expression of the inducible form of NO synthase (iNOS) and thus NO production (16)(17)(18). We measured NO production of islets isolated from Ucp2-WT and Ucp2-KO mice treated or not with IL-1␤ and IFN-␥ for 48 h, as previously described (19).…”