MST1 is a key regulator of beta cell apoptosis and dysfunction in diabetes

Abstract

Apoptotic cell death is a hallmark of the loss of insulin producing beta-cells in all forms of diabetes mellitus. Current treatment fails to halt the decline in functional beta-cell mass. Strategies to prevent beta-cell apoptosis and dysfunction are urgently needed. Here, we identified Mammalian Sterile 20-like kinase 1 (MST1) as a critical regulator of apoptotic beta-cell death and function. MST1 was strongly activated in beta-cells under diabetogenic conditions and correlated with beta-cell apoptosis. MST1 specifically induced the mitochondrial-dependent pathway of apoptosis in beta-cells through up-regulation of the BH3-only protein Bim. MST1 directly phosphorylated PDX1 at Thr11, resulting in its ubiquitination, degradation and impaired insulin secretion. Mst1 deficiency completely restored normoglycemia, beta-cell function and survival in vitro and in vivo. We show MST1 as novel pro-apoptotic kinase and key mediator of apoptotic signaling and beta-cell dysfunction, which may serve as target for the development of novel therapies for diabetes.