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

Abstract

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. Their upregulation and activation in β-cells under conditions of both type 1 and type 2 diabetes directly correlates with β-cell failure; β-cell death and loss of insulin secretory function through disturbance of cell survival control mechanisms. 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. PHLPP1 deletion in severely diabetic leptin receptor-deficient db/db mice restored normoglycemia and β-cell area through increased β-cell proliferation and reduced β-cell apoptosis. The beneficial effects of PHLPP1 deficiency in a severe mouse model of obesity and diabetes make PHLPP a new target for β-cell-directed diabetes therapy.

Phlpp1 Expression in Osteoblasts Plays a Modest Role in Bone Homeostasis

“…For instance, Phlpp1 inhibits the systemic actions of insulin and reduces survival of β cells within the pancreas, which could indirectly affect skeletal development and degeneration. (30)(31)(32) Prior work also supports that Phlpp1 ablation limits chondrocyte proliferation and endochondral ossification (18,29) but limits articular cartilage and intervertebral disc degeneration. (33,34) Likewise, Phlpp1 deficiency promotes inflammatory responses of immune cells by enhancing STAT1-dependent signaling.…”