Résumé
Pancreatic β-cell failure is the key pathogenic element of the complex metabolic deterioration in type 2 diabetes (T2D); its underlying pathomechanism is still elusive. Here, we identify pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2 (PHLPP1/2) as phosphatases whose upregulation leads to β-cell failure 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. Genetic 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 study presents PHLPPs as targets for functional regenerative therapy of pancreatic β cells in diabetes.
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•PHLPP1/2 are highly elevated in metabolically stressed β cells in diabetes•Metabolic-stress-induced mTORC1 hyper-activation leads to PHLPP upregulation•PHLPPs regulate β-cell survival-dependent kinases AKT and MST1•PHLPP inhibition restores glycemia, β-cell survival, and function
Lupse et al. show that chronic metabolic stress and high sugar in diabetes leads to hyper-activation of the metabolism-control pathway mTORC1 and initiation of a triangle loop of cellular survival control by the phosphatase PHLPP. PHLPP inhibits pro-survival AKT, activates pro-apoptotic MST1, and ultimately leads to β-cell death and dysfunction.