The aim of our research group is to investigate the molecular mechanisms of pancreatic beta cell dysfunction and destruction in the pathogenesis of type 1 and type 2 diabetes mellitus (T1DM and T2DM). In particular we are interested in the involvement of reactive oxygen species (ROS) in these pathogenic processes and their importance for oxidative insulin folding and its dysfunction.
Pancreatic beta cells are characterised by an extraordinary low expression of hydrogen peroxide-inactivating enzymes and therefore beta cells are particularly susceptible to the accumulation of hydrogen peroxide and various other ROS.
The autoimmune destruction of pancreatic beta cells during the pathogenesis of T1DM is mediated in part by pro-inflammatory cytokines (e.g. IL-1ß, TNF-α, and IFN-γ), which activate intracellular signal pathways finally leading to the apoptotic destruction of the insulin-secreting cells. ROS generation in this destruction process is caused by gene expression changes, inhibition of enzymes or changes of the cellular redox homeostasis. In this scenario mitochondria are the central ROS-generating compartment, but also the target of cytokine-mediated toxicity.
During the initial course of T2DM, however, beta cells can compensate the insulin resistance of peripheral tissues through a massive increase of their insulin secretion capacity. Nevertheless, in most affected patients a progressive loss of beta cell function and also a loss of beta cell mass can be observed. This has been linked to the enormous cellular work load resulting from the elevated insulin synthesis rate, which is connected to increased oxidative insulin folding and consequently increased luminal hydrogen peroxide generation. Furthermore, this ROS accumulation has been associated with a reduction of protein folding efficacy, initiation of oxidative ER stress, and loss of beta cell function and viability
Our aims are:
- Mechanisms of beta cell damage by ROS in the presence of pro-inflammatory cytokines (T1DM)
- Characterisation of signaling and metabolic pathways leading to elevated ROS generation
- Identification and characterisation of ROS sources under typical T1DM and T2DM conditions
- Effects of ROS on protein folding efficacy and proteostasis in beta cells
- Importance of antioxidative enzymes, expressed in different cell organelles, for the protection of beta cells