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Section III: Inflammation and β-Cell Death

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

Many Differences, Few Similarities

  1. Miriam Cnop12,
  2. Nils Welsh3,
  3. Jean-Christophe Jonas4,
  4. Anne Jörns56,
  5. Sigurd Lenzen6 and
  6. Decio L. Eizirik1
  1. 1Laboratory of Experimental Medicine, Faculty of Medicine, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
  2. 2Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
  3. 3Department of Medical Cell Biology, Uppsala University, Biomedicum, Uppsala, Sweden
  4. 4Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain (UCL), Brussels, Belgium
  5. 5Centre of Anatomy, Hannover Medical School, Hannover, Germany
  6. 6Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany
  1. Address correspondence and reprint requests to Dr. Miriam Cnop, Laboratory of Experimental Medicine, Université Libre de Bruxelles (ULB), Route de Lennik 808, CP-618, 1070 Brussels, Belgium. E-mail: mcnop{at}ulb.ac.be
Diabetes 2005 Dec; 54(suppl 2): S97-S107. https://doi.org/10.2337/diabetes.54.suppl_2.S97
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Many Differences, Few Similarities

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.

  • 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
  • IκB, inhibitory κB
  • 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

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted March 30, 2005.
    • Received February 23, 2005.
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Mechanisms of Pancreatic β-Cell Death in Type 1 and Type 2 Diabetes
Miriam Cnop, Nils Welsh, Jean-Christophe Jonas, Anne Jörns, Sigurd Lenzen, Decio L. Eizirik
Diabetes Dec 2005, 54 (suppl 2) S97-S107; DOI: 10.2337/diabetes.54.suppl_2.S97

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Mechanisms of Pancreatic β-Cell Death in Type 1 and Type 2 Diabetes
Miriam Cnop, Nils Welsh, Jean-Christophe Jonas, Anne Jörns, Sigurd Lenzen, Decio L. Eizirik
Diabetes Dec 2005, 54 (suppl 2) S97-S107; DOI: 10.2337/diabetes.54.suppl_2.S97
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    • SIMILARITIES AND DIFFERENCES BETWEEN THE MECHANISMS OF β-CELL DEATH IN TYPE 1 DIABETES
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  • Mechanisms of β-Cell Death in Type 2 Diabetes
  • Interleukin-6 and Diabetes
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