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.

Loss of functional pancreatic β cells is a hallmark of both type 1 and 2 diabetes. Identifying the pathways that promote β cell proliferation and/or block β cell apoptosis is a potential strategy for diabetes therapy. The transcriptional coactivator Yes-associated protein (YAP), a major downstream effector of the Hippo signaling pathway, is a key regulator of organ size and tissue homeostasis by modulating cell proliferation and apoptosis. YAP is not expressed in mature primary human and mouse β cells. We aimed to identify whether reexpression of a constitutively active form of YAP promotes β cell proliferation/survival. Overexpression of YAP remarkably induced β cell proliferation in isolated human islets, while β cell function and functional identity genes were fully preserved. The transcription factor forkhead box M1 (FOXM1) was upregulated upon YAP overexpression and necessary for YAP-dependent β cell proliferation. YAP overexpression protected β cells from apoptosis triggered by multiple diabetic conditions. The small redox proteins thioredoxin-1 and thioredoxin-2 (Trx1/2) were upregulated by YAP; disruption of the Trx system revealed that Trx1/2 was required for the antiapoptotic action of YAP in insulin-producing β cells. Our data show the robust proproliferative and antiapoptotic function of YAP in pancreatic β cells. YAP reconstitution may represent a disease-modifying approach to restore a functional β cell mass in diabetes.

Over the last 2 decades, induced pluripotent stem cells (iPSCs) have had various potential applications in various medical research areas, from personalized medicine to disease treatment. Different cellular resources are accessible for iPSC generation, such as keratinocytes, skin fibroblasts, and blood or urine cells. However, all these sources are somatic cells, and we must make several changes in a somatic cell’s transcriptome and chromatin state to become a pluripotent cell. It has recently been revealed that cancer cells can be a new source of iPSCs production. Cancer cells show similarities with iPSCs in self-renewal capacity, reprogramming potency, and signaling pathways. Although genetic abnormalities and potential tumor formation in cancer cells pose a severe risk, reprogrammed cancer-induced pluripotent stem cells (cancer-iPSCs) indicate that pluripotency can transiently overcome the cancer phenotype. This review discusses whether cancer cells can be a preferable source to generate iPSCs.

Bone marrow mesenchymal stromal cells (BM-MSCs) have anti-inflammatory and pro-survival properties. Naturally, they do not express human leukocyte antigen class II surface antigens and have immunosuppressive capabilities. Together with their relatively easy accessibility and expansion, they are an attractive tool for organ support in transplantation and regenerative therapy. Autologous BM-MSC transplantation alone or together with transplanted islets improves β-cell function, graft survival, and glycemic control in diabetes. Albeit MSCs’ capacity to transdifferentiate into β-cell is limited, their protective effects are mediated mainly by paracrine mechanisms through BM-MSCs circulating through the body. Direct cell–cell contact and spontaneous fusion of BM-MSCs with injured cells, although at a very low rate, are further mechanisms of their supportive effect and for tissue regeneration. Diabetes is a disease of long-term chronic inflammation and cell therapy requires stable, highly functional cells. Several tools and protocols have been developed by mimicking natural fusion events to induce and accelerate fusion in vitro to promote β-cell-specific gene expression in fused cells. BM-MSC-islet fusion before transplantation may be a strategy for long-term islet survival and improved function. This review discusses the cell-protective and anti-inflammatory characteristics of BM-MSCs to boost highly functional insulin-producing cells in vitro and in vivo, and the efficacy of their fusion with β-cells as a path to promote β-cell regeneration.