Type 1 diabetes (T1D) and type 2 diabetes (T2D) are both hallmarked by loss of insulin-producing pancreatic beta cells. Kathrin Maedler and her colleagues now show that the kinase MST1 is upregulated by diabetic conditions in beta cells, resulting in their dysfunction and their apoptosis. They also show that genetic knockout of the gene encoding Mst1 results in protection from diabetes in T1D and T2D mouse models. Apoptotic cell death is a hallmark of the loss of insulin-producing beta cells in all forms of diabetes mellitus. Current treatments fail to halt the decline in functional beta cell mass, and 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. Under diabetogenic conditions, MST1 was strongly activated in beta cells in human and mouse islets and specifically induced the mitochondrial-dependent pathway of apoptosis through upregulation of the BCL-2 homology-3 (BH3)-only protein BIM. MST1 directly phosphorylated the beta cell transcription factor PDX1 at T11, resulting in the latter's ubiquitination and degradation and thus in impaired insulin secretion. MST1 deficiency completely restored normoglycemia, beta cell function and survival in vitro and in vivo. We show MST1 as a proapoptotic kinase and key mediator of apoptotic signaling and beta cell dysfunction and suggest that it may serve as target for the development of new therapies for diabetes.

Hippo signaling is an evolutionarily conserved pathway that critically regulates development and homeostasis of various tissues in response to a wide range of extracellular and intracellular signals. As an emerging important player in many diseases, the Hippo pathway is also involved in the pathophysiology of diabetes on the level of the pancreatic islets. Multiple lines of evidence uncover the importance of Hippo signaling in pancreas development as well as in the regulation of β-cell survival, proliferation, and regeneration. Hippo therefore represents a potential target for therapeutic agents designed to improve β-cell function and survival in diabetes. In this review, we summarize recent data on the regulation of the Hippo signaling pathway in the pancreas/in pancreatic islets, its functions on β-cell homeostasis in physiology and pathophysiology, and its contribution toward diabetes progression. The current knowledge related to general mechanisms of action and the possibility of exploiting the Hippo pathway for therapeutic approaches to block β-cell failure in diabetes is highlighted.