PHLPP1 deletion restores pancreatic β-cell survival and normoglycemia in the db/db mouse model of obesity-associated diabetes

The Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs) are novel therapeutic targets for the restoration of beta-cell survival and function in diabetes. Their upregulation and activation in beta-cells under conditions of both type 1 and type 2 diabetes directly correlates with beta-cell failure; beta-cell death and loss of insulin secretory function through disturbance of cell survival control mechanisms. PHLPPs directly dephosphorylate and regulate activities of beta-cell survival-dependent kinases AKT and MST1 constituting a regulatory triangle loop to control beta-cell apoptosis. PHLPP1 deletion in severely diabetic leptin receptor-deficient db/db mice restored normoglycemia and beta-cell area through increased beta-cell proliferation and reduced beta-cell apoptosis. The beneficial effects of PHLPP1 deficiency in a severe mouse model of obesity and diabetes make PHLPP a new target for beta-cell-directed diabetes therapy.

Automated summary

PHLPPs play a role in restoring beta-cell function and survival in diabetes. Their upregulation and activation are associated with beta-cell dysfunction, affecting the cell's ability to survive through control mechanisms.