Glucolipotoxicity‐induced p21 suppresses pro‐survival signaling in pancreatic β cells (1108.9)

Type 2 diabetes manifests from peripheral insulin resistance and a loss of functional β cell mass due to decreased β cell function, survival, or proliferation. The glucolipotoxic environment in the diabetic milieu activates a stress response in β cells, resulting in cell death and decreased survival through various mechanisms. One key player implicated in β cell dysfunction is FOXO‐1, a transcription factor phosphorylated and inhibited by the pro‐survival kinase Akt. Interestingly, palmitate in combination with high glucose induced expression of p21, a cell cycle inhibitor that activates the intrinsic apoptotic pathway and reduces Akt cell survival signaling. The molecular mechanism by which p21 activates apoptosis in β cells during metabolic stress is still unknown. We hypothesized that p21‐mediated suppression of Akt leads to FOXO‐1 activation, ultimately resulting in the expression of pro‐apoptotic factors. To investigate the molecular events that p21 acts through to increase death and reduce cell survival, we adenovirally overexpressed p21 in isolated islets and 832/13 cells. p21 overexpression increased phosphorylation of the stress‐activated protein kinase JNK. In contrast, FOXO‐1 phosphorylation was suppressed, indicating activation of FOXO‐1. We are actively investigating whether a constitutively‐active Akt will reverse this p21‐mediated phenomena of FOXO‐1 activation. Therefore, we propose that p21‐mediated inactivation of Akt leads to cell death via JNK and FOXO1 activation. Our findings suggest a molecular mechanism by which metabolic stress‐ or glucolipotoxicity‐induced p21 expression leads to β cell death‐a mechanism that could potentially be targeted to protect β cell mass. Grant Funding Source : Supported by NIH grant DK078732 and William Townsend Porter Fellowship from APS