Novo Nordisk fonden - Molecular mechanisms of the protective effect of iron depletion on inflammation- and glucolipotoxicity-mediated pancreatic beta-cell damage

Project: Research

Project Details

Description

Diabetes can occur when pancreatic beta-cells fail to secrete insulin with timing and in quantities appropriate to maintain metabolic homeostasis. Inflammation and metabolic stress reduce beta-cell function in vitro and it is believed to impair insulin secretory capacity and contribute to progressive loss of beta-cell mass. Both proinflammatory cytokines and elevated levels of glucose and free fatty acids (glucolipotoxicity) induce expression and activation of divalent metal transporter 1 (DMT1), promoting iron uptake, production of reactive oxygen species (ROS) and thereby targeting pancreatic beta-cells to extensive oxidative stress and subsequently apoptosis. How inflammation and metabolic stress signal DMT-1 expression and the down-stream links between iron-mediated oxidative stress and beta-cell dysfunction and death is poorly understood. Taking advantage of islets from inducible beta-cell specific DMT1 knock-out (KO) mice, we will be able to qualitatively and quantitatively investigate the regulated proteins and multiple PTMs (including phosphorylation, cysteine oxidationand glycosylation) and predict PTMs cross- talking events essential for cellular signaling in islets exposed to cytokines and glucolipotoxic conditions using our newly developed comprehensive multiple PTMomics strategy. This will reveal novel pharmacological targets in the beta-cell signaling pathways and underlying mechanisms bridging inflammation, glucolipotoxicity, iron uptake and oxidative stress leading to diabetes mellitus.
StatusFinished
Effective start/end date01/01/201730/11/2019