Modulating the hippo pathway as novel strategy for beta-cell-directed therapy in diabetes

Pancreatic β-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D). The Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs) are novel therapeutic targets for the restoration of β-cell survival and function in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic β-cells. Sustained hyper-activation of mechanistic target of rapamycin complex 1 (mTORC1) is the primary mechanism of the PHLPP upregulation linking chronic metabolic stress to ultimate β-cell death. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1, constituting a regulatory triangle loop to control β-cell apoptosis. Inhibition of PHLPPs markedly improves β-cell survival and function in experimental models of diabetes in vitro, in vivo, and in primary human T2D islets. Our research defines an important mechanism of β-cell failure in diabetes and demonstrates the functional significance of targeting PHLPPs in restoring pancreatic β-cell mass in diabetes.