Mechanisms of Pancreatic β-Cell Death in Type 1 and Type 2 Diabetes

Abstract

Type 1 and type 2 diabetes are characterized by progressive β-cell failure. Apoptosis is probably the main form of β-cell death in both forms of the disease. It has been suggested that the mechanisms leading to nutrient- and cytokine-induced β-cell death in type 2 and type 1 diabetes, respectively, share the activation of a final common pathway involving interleukin (IL)-1β, nuclear factor (NF)-κB, and Fas. We review herein the similarities and differences between the mechanisms of β-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-1β, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ. IL-1β and/or TNF-α plus IFN-γ induce β-cell apoptosis via the activation of β-cell gene networks under the control of the transcription factors NF-κB and STAT-1. NF-κB activation leads to production of nitric oxide (NO) and chemokines and depletion of endoplasmic reticulum (ER) calcium. The execution of β-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 β-cell dysfunction and may induce β-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-1β, NF-κB, or inducible nitric oxide synthase in rat or human β-cells in vitro or in vivo in Psammomys obesus. FFAs may cause β-cell apoptosis via ER stress, which is NF-κB and NO independent. Thus, cytokines and nutrients trigger β-cell death by fundamentally different mechanisms, namely an NF-κB–dependent mechanism that culminates in caspase-3 activation for cytokines and an NF-κB–independent mechanism for nutrients. This argues against a unifying hypothesis for the mechanisms of β-cell death in type 1 and type 2 diabetes and suggests that different approaches will be required to prevent β-cell death in type 1 and type 2 diabetes.