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Sirtuin 1 and angiotensin II as inflammatory modulators in the development of diabetes

Thienel, Constanze. Sirtuin 1 and angiotensin II as inflammatory modulators in the development of diabetes. 2015, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_11545

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Abstract

Diabetes mellitus is a multifactorial metabolic disease characterized by elevated blood glucose due to pancreatic β-cell dysfunction and insulin resistance. The mechanisms of the initiation and progression of the disease are not fully understood but there is increasing evidence that inflammation plays a crucial effector role in the development of both type 1 and type 2 diabetes (T1D and T2D), leading to β-cell damage and β-cell death. Remaining β-cells compensate for the higher insulin demand until they fail. In T1D, additionally dysregulated immune tolerance along with autoantibodies against self-antigens leads to β-cell destruction. In this work, we are focusing on the role of two inflammatory modulators in the development of diabetes, angiotensin II (Ang II) and sirtuin 1 (SIRT1).
Ang II as central player of the renin-angiotensin-system (RAS) is classically known as regulator for local and systemic blood flow, body fluid homeostasis and electrolyte balance. However, after the discovery of a pancreatic local RAS, the connection between RAS blockage and the reduction of new onset diabetes has been found. In this work, we show that Ang II induces islet inflammation, β-cell dysfunction and β-cell death in rodent and human islets and in a mouse model of T2D, independently of vasoconstriction. Blockage of the master regulating pro-inflammatory cytokine interleukin-1β (IL-1β) by specific antibodies improved glucose tolerance and islet inflammation in Ang II-treated mice. This provides an additional rationale for the treatment of type 2 diabetes with anti-IL-1β antibodies.
The NAD+ dependent histone and protein deacetylase SIRT1, the closest homolog to Sir2 in yeast, has attracted interest as a regulator of stress responses and longevity. The enzyme is implicated in various age-dependent diseases because of its potential to modulate cellular processes of metabolism and immune responses. In this work, we demonstrate an enhanced metabolic and islet activity along with reduced regulatory T-cells in a knock-in mouse model carrying a SIRT1 mutation, which is associated with familial autoimmune diabetes and colitis. Further, we show the beneficial influence of β-cell specific SIRT1 knock-out in the induction of T1D in mice. We hypothesize that context dependent overactivation by the mutated SIRT1 leads to enhanced insulin secretion, islet inflammation and an autoimmune-like phenotype along with reduced regulatory T-cells in our SIRT1 knock-in mice.
In turn, β-cell specific deletion of SIRT1 protects from the development of T1D, possibly by the induction of a “β-cell rest” and therefore islet recovery. Accordingly, SIRT1 inhibition and not activation in the context of T1D may have beneficial effects.
Altogether, immunomodulatory treatments by targeting inflammatory players such as Ang II or SIRT1 may have therapeutical value in the context of autoimmune diseases and diabetes.
Advisors:Donath, Marc Y. and Handschin, Christoph
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Diabetes Research (Donath)
Item Type:Thesis
Thesis no:11545
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:59
Deposited On:08 Feb 2016 15:09

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