DYRK1A aggravates β cell dysfunction and apoptosis by promoting the phosphorylation and degradation of IRS2

Abstract In this study, we aimed to investigate the role of dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), which is one of the most important regulators of Alzheimer's disease development, in islet β cell dysfunction and apoptosis. We found significantly increased expression of DYRK1A in both the hippocampus and pancreatic islets of APPswe/PS1ΔE9 transgenic mice than in wild-type littermates. Furthermore, we observed that the overexpression of DYRK1A greatly aggravated β cell apoptosis. Most importantly, we found that DYRK1A directly interacted with insulin receptor substrate-2 (IRS2) and promoted IRS2 phosphorylation, leading to the proteasomal degradation of IRS2 and promotion of β cell dysfunction and apoptosis. These findings suggested that DYRK1A is a potential drug target in diabetes mellitus.