The role of oxidative ER stress in the dysregulation of ER calcium homeostasis and β-cell failure under type 2 diabetes metabolic conditions

• Applicant: Dr. Ilir Mehmeti
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 459463862

Type 2 diabetes mellitus (T2DM) is a heterogeneous and chronically progressive metabolic disease of epidemic proportions with increasing prevalence also in children and adolescents. This type of the disease is characterized by insulin resistance of the target organs and defective insulin secretion. Insulin resistance can be compensated in the phase of impaired glucose tolerance by hyperinsulinemia and β-cell hyperplasia. However, during the course of T2DM a progressive β-cell dysfunction and a decline of the functional β-cell mass occurs. Consequently, β-cells cannot cope with the increasing insulin demand and T2DM with increased blood glucose concentrations becomes overt. β-cell failure and the loss of functional β-cell mass have been associated with an excessive formation of reactive oxygen species (ROS). These cell-damaging compounds can be formed due to the metabolism of supraphysiological concentrations of glucose and free fatty acids (glucolipotoxicity) and during the oxidative protein folding in the ER. Especially in the ER, the amount of H2O2 can increase massively during hyperglycemia due to compensatorily increased insulin biosynthesis and a concomitant increased protein folding rate. Elevated H2O2 concentrations are associated with the disruption of ER redox homeostasis, which is crucial for oxidative protein folding, the associated induction of chronic ER stress, and mitochondrial dysfunction. However, a causal involvement of luminal H2O2 in the reduction of β-cell function and mass under glucolipotoxic conditions is still unconfirmed. Therefore, the main focus of this project proposal will be on oxidative ER stress. In particular, the relevance of the generation and detoxification of luminal H2O2 for the dysregulation of ER calcium homeostasis and the crosstalk between ER and mitochondria under glucolipotoxic conditions will be investigated in detail. Recently, cellular organelles are no longer considered static and isolated, but rather dynamic compartments. Therefore, in selected experiments the influence of luminal H2O2 and its elimination on the mediators of ER-mitochondria interactions (mitochondria-associated ER membrane) will be elucidated. In addition, new candidate genes and key signal transduction pathways involved in oxidative ER stress cell damage will be identified through the use of different ER stress models. A detailed knowledge of the causal relationships between the occurrence of oxidative ER stress and interorganelle interactions will represent the basis for future intervention strategies to preserve pancreatic β-cells and their function.

• DFG Programme: Research Grants