Glucose stimulation of, pancreatic beta cells (PBCs) results in the release of insulin, which is subsequently transported around the body, where it regulate carbohydrate metabolism. The secretion of insulin after glucose stimulation takes place via a calcium-dependent process called exocytosis, which in beta cells occurs in two phases (biphasic) and continues after the end of stimulation. After glucose stimulation of PBCs glucose is taken up and degraded, resulting in ATP generation and a depolarization of the plasma membrane. This depolarization results in an influx of calcium (Ca2+) ions into the cell. This influx of Ca2+ causes an activation of kinases and phosphatases, which control phosphorylation-dependent signaling pathways within the cell. This has many consequences, including the cleavage of pro-insulin in insulin-granules (vesicles containing insulin and other molecules), which results in the release of insulin by means of exocytosis and modulation of gene expression. Recently,there has been an increasing focus on other post-translational modifications (PTMs) than phosphorylation, such as lysine acetylation, which could have a significant influence on signaling pathways in the cell. In the present study we will characterize the signaling pathways involved in the initial release of insulin from PBCs using novel quantitative strategies for PTMomics. Defects in exocytosis or other signaling mechanisms can lead to a decrease in the release of insulin from the beta cells and subsequently diabetes. Therefore, a thorough investigation of the signaling mechanisms behind the glucose-mediated release of insulin will not only provide new knowledge about the way beta cells secrete insulin, but may also offer new targets for therapeutic intervention.
|Effective start/end date||01/01/2016 → 31/12/2016|