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Inflammatory mediators and islet β-cell failure: a link between type 1 and type 2 diabetes

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Abstract

Pancreatic islet β-cell death occurs in type 1 and 2 diabetes mellitus, leading to absolute or relative insulin deficiency. β-cell death in type 1 diabetes is due predominantly to autoimmunity. In type 2 diabetes β-cell death occurs as the combined consequence of increased circulating glucose and saturated fatty acids together with adipocyte secreted factors and chronic activation of the innate immune system. In both diabetes types intra-islet inflammatory mediators seem to trigger a final common pathway leading to β-cell apoptosis. Therefore anti-inflammatory therapeutic approaches designed to block β-cell apoptosis could be a significant new development in type 1 and 2 diabetes.

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Abbreviations

DD :

Death domain

ECSIT :

Evolutionary conserved signaling intermediate in Toll/IL-1 pathways

ER :

Endoplasmic reticulum

ERK :

Extracellular signal-regulated kinase

FADD :

Fas-associated death domain

FasL :

Fas ligand

FFA :

Free fatty acid

FLIP :

Fas-associated death domain-like IL-1β converting enzyme inhibitory protein

IFN :

Interferon

IKK :

IκB kinase

IL :

Interleukin

IL-1R1 :

IL-1 type 1 receptor

IL-1Ra :

IL-1 receptor antagonist

iNOS :

Inducible nitric oxide synthase

IRAK :

IL-1R activated kinase

IRF :

Interferon regulatory factor

IκB :

Inhibitory κB protein

JAK :

Janus tyrosine kinases

JNK :

c-jun N-terminal kinase

MAP :

Mitogen-activated protein

MAPK :

Mitogen-activated protein kinase

MEKK :

MAPK/ERK kinase kinase

MORT :

Mediator of receptor induced toxicity

NF :

Nuclear transcription factor

NOD :

Nonobese diabetic

Pdx :

Pancreatic duodenal homeobox factor

PKC :

Protein kinase C

ROS :

Reactive oxygen species

SAPK :

Stress-activated protein kinases

SERCA :

Sarco-/endoplasmic reticulum Ca2+ ATPase

STAT :

Signal transducer and activator of transcription

TAK :

Transforming growth factor β-activated kinase

TNF :

Tumor necrosis factor

TRADD :

TNF receptor associated death domain

TRAF :

TNF receptor associated factor

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Acknowledgements

This work was supported in part by the Juvenile Diabetes Research Foundation International Grant # 4-2002-457, the Danish Diabetes Association and Novo Nordisk (J.S., T.M.P.) and by the Swiss National Science Foundation Grants #3200-067049.01 and PP00B-68874/1 and by the Max Cloetta Foundation (M.Y.D.).

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Authors and Affiliations

  1. Division of Endocrinology and Diabetes, University Hospital, 8091, Zurich, Switzerland

    Marc Y. Donath & Kathrin Maedler

  2. Steno Diabetes Center, 2820, Gentofte, Denmark

    Joachim Størling & Thomas Mandrup-Poulsen

  3. Department of Molecular Medicine, Rolf Luft Center for Diabetes Research, Karolinska Institute, 17176, Stockholm, Sweden

    Thomas Mandrup-Poulsen

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  1. Marc Y. Donath
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  2. Joachim Størling
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  4. Thomas Mandrup-Poulsen
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Correspondence to Marc Y. Donath.

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Donath, M.Y., Størling, J., Maedler, K. et al. Inflammatory mediators and islet β-cell failure: a link between type 1 and type 2 diabetes. J Mol Med 81, 455–470 (2003). https://doi.org/10.1007/s00109-003-0450-y

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