Oxidative Stress-Induced Protein Damage in β-cell Secretory Dysfunction

Center University of Colorado Denver
Award Year 2022
Pilot Study Oxidative Stress-Induced Protein Damage in β-cell Secretory Dysfunction
Awardee Jefferson Knight PhD ORCiD

Inflammation produces high levels of reactive oxygen species such as hydrogen peroxide, superoxide, and their downstream products including reactive lipid aldehydes. Such oxidative stress is a key contributor to β-cell failure in both type 1 and type 2 diabetes (T1D and T2D). In T1D, β-cells are damaged due to autoimmune inflammation and lose the ability to secrete insulin prior to their eventual destruction. In T2D, oxidative stress arising in part from inflammatory cytokine signaling is also known to occur prior to β-cell failure, although the molecular mechanisms remain poorly understood. In this project, we will test the hypothesis that oxidative stress impairs insulin secretion via irreversible post-translational modification to membrane trafficking proteins. The project is a collaboration between the principal investigator (Dr. Knight), an established secretory protein biochemist, and Dr. Colin Shearn in the Department of Pediatrics, an expert in oxidative stress and inflammation. In this pilot study, we will identify protein targets of reactive lipid aldehydes in β-cell lines and in cytokine-treated islets using cutting-edge proteomic approaches, and we will quantify the effects of protein modification on secretory function. Our preliminary results suggest that key proteins in the insulin secretory pathway are susceptible to irreversible modification by lipid aldehydes, and that this modification can begin to inhibit insulin secretion within minutes. Results from this basic science study could have significant implications for detecting and understanding early events in β-cell failure that lead to diabetes.