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Pancreatic β-cell identity and metabolic consequences following anti-inflammatory therapy in type 2 diabetes

Nordmann, Thierry. Pancreatic β-cell identity and metabolic consequences following anti-inflammatory therapy in type 2 diabetes. 2016, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_11697

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Abstract

Type 2 diabetes mellitus (T2DM) is a metabolic disorder, characterized by the inability of the insulin secreting β-cells to compensate for insulin resistance. Increasing evidence points towards a role of the immune system in this development. Furthermore, ß-cell dedifferentiation has recently been proposed as a mechanism underlying β-cell failure in T2DM. Therefore we investigated whether cytokines may induce ß-cell dedifferentiation and whether anti-inflammatory drugs, alone or in combination, may improve insulin secretion.
We observed that IL-1ß drives ß-cell dedifferentiation in both human and mouse pancreatic islets. Interestingly, ß-cell identity maintaining transcription factor FoxO1 was downregulated upon IL-1ß exposure. To test the relevance of IL-1ß induced dedifferentiation in vivo, 3 animal models of T2DM were investigated for the presence of ß-cell dedifferentiation and the impact of IL-1ß antagonism. All 3 models showed signs of islet-inflammation and ß-cell dedifferentiation. However, IL-1ß antagonism failed to restore reduced expression of key ß-cell identity markers, while partially improving glycemia. Thus, while IL-1ß triggers dedifferentiation and dysfunction in vitro, glycemic improvement through IL-1ß antagonism appears not to be related to ß-cell redifferentiation in vivo. In addition, while separate treatment of anti-IL-1ß, anti-TNFα and NF-κB suppressing salicylate showed favorable effects on glycemia, our data do not show a meaningful additive effect of IL-1ß inhibition together with TNFα antagonism or with salicylate.
Finally, focusing on the adaptive side of inflammation, we tested whether the physiological, exercise-induced and muscle-derived IL–6 is regulated by the IL–1 system. In a double blind, crossover study in humans, we could show that the beneficial effect of muscle-induced IL–6 is not meaningfully affected by IL–1 antagonism.
Advisors:Donath, Marc and Hess, Christoph
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Endokrinologie / Diabetologie > Endokrinologie, Diabetologie und Metabolismus (Donath)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Endokrinologie / Diabetologie > Endokrinologie, Diabetologie und Metabolismus (Donath)
Item Type:Thesis
Thesis no:11697
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (viii, 112 Seiten)
Language:English
Identification Number:
Last Modified:24 Jan 2017 09:55
Deposited On:29 Aug 2016 08:39

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