The transcription coactivator Yes-associated protein (YAP) influences beta cell proliferation and diabetes

Beta cell failure is a hallmark of both type 1 and type 2 diabetes. The mechanisms of the initiation of beta cell dysfunction and beta cell death are not completely understood. Investigating the mechanism of action of various signal molecules involved in beta cell apoptosis and proliferation can result in novel targets for diabetes treatment. The Hippo pathway is a vital cascade that plays a fundamental role during cell and organ development. It also regulates beta cell proliferation, apoptosis, and differentiation through its main components including NF2, MST1/2, LATS1/2 and YAP. Yes associated protein (YAP) is a main downstream target of Large Tumor Suppressor (LATS) 1/2 and transcriptional co-activator that enhances expression of several genes by interaction with TEAD transcription factor.
YAP is highly expressed during pancreas development. As soon as endocrine islet cells origin, YAP is limited to exocrine and duct cells and excluded from the endocrine part. Also later in mature beta cells, I found that YAP is not expressed.
In my doctoral thesis I asked the question whether YAP re-expression can restore the almost absent proliferative capacity in mature beta cells. We also clarified the effect of YAP on pancreatic beta cells in both physiological and diabetic states.
Therefore, I re-expressed the active form of YAP specifically in beta cells and in human islets. Indeed, I found that YAP re-expression enhances beta cell proliferation without changing beta cell function and identity. The Forkhead Box M1 (FOXM1)-YAP crosstalk plays a crucial role in switching on beta cell proliferation, regeneration and cell cycle progression. In parallel, YAP re-expression has an anti-apoptotic effect on beta cells under diabetic conditions.
In a second part of this study, I analyzed the differential expression of mechanistic target of rapamycin complexes (mTORC), master regulators of nutritional status at both cellular and organismic levels, in human and mouse diabetic islets under diabetogenic conditions. Our results revealed a hyperactivity of mTORC1 in human islets from patients with type 2 diabetes. Moreover, specific mTORC1 inhibition can restore beta cell function in diabetes.
Altogether, my data suggest that high metabolic overload leads to mTORC1 hyperactivity; such beta cell stress impairs beta cell function and survival during the progression of diabetes. As beta cells have lost important pro-proliferative factors during maturation and identity, such as YAP, they are unable to compensate for a chronic high metabolic demand. The results of my work propose that a transient overexpression of YAP restores beta cell proliferation during stress and could stand as future beta cell regeneration therapy for functional beta cell mass expansion. It could further be used as tool for cell replacement therapy to restore beta cell survival during islet transplantation.