Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes -: Many differences, few similarities

Type 1 and type 2 diabetes are characterized by progressive beta-cell failure. Apoptosis is probably the main form of beta-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced beta-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1 beta, nuclear factor (NF)-kappa B, and Fas. We review herein the similarities and differences between the mechanisms of beta-cell death in type 1 and type 2 diabetes. In the insulitis lesion in type 1 diabetes, invading immune cells produce cytokines, such as IL-1 beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma. IL-1 beta and/or TNF-alpha. plus IFN-gamma induce beta-cell apoptosis via the activation of beta-cell gene networks under the control of the transcription factors NF-kappa B and STAT-1. NF-kappa B activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of beta-cell death occurs through activation of mitogen-activated protein kinases, via triggering of ER stress and by the release of mitochondrial death signals. Chronic exposure to elevated levels of glucose and free fatty acids (FFAs) causes beta-cell dysfunction and may induce beta-cell apoptosis in type 2 diabetes. Exposure to high glucose has dual effects, triggering initially glucose hypersensitization and later apoptosis, via different mechanisms. High glucose, however, does not induce or activate IL-1 beta, NF-kappa B, or inducible nitric oxide synthase in rat or human beta-cells in vitro or in vivo in Psammomys obesus. FFAs may cause beta-cell apoptosis via ER stress, which is NF-kappa B and NO independent. Thus, cytokines and nutrients trigger theta-cell death by fundamentally different mechanisms, namely an NF-kappa B-dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-kappa B-independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of beta-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent beta-cell death in type 1 and type 2 diabetes.