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

Many Differences, Few Similarities

¹ Laboratory of Experimental Medicine, Faculty of Medicine, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
² Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
³ Department of Medical Cell Biology, Uppsala University, Biomedicum, Uppsala, Sweden
⁴ Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain (UCL), Brussels, Belgium
⁵ Centre of Anatomy, Hannover Medical School, Hannover, Germany
⁶ Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

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

Abbreviations: ATF, activating transcription factor; CHOP, C/EBP (CCAAT/enhancer binding protein) homologous protein; ER, endoplasmic reticulum; ERK, extracellular signal–regulated kinase; FACS, fluorescence-activated cell sorting; FFA, free fatty acid; GIIS, glucose-induced insulin secretion; IB, inhibitory B; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; NF, nuclear factor; SOCS, suppressor of cytokine signaling; TNF, tumor necrosis factor

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