| First Author | Lupse B | Year | 2021 |
| Journal | Cell Rep | Volume | 36 |
| Issue | 5 | Pages | 109490 |
| PubMed ID | 34348155 | Mgi Jnum | J:324786 |
| Mgi Id | MGI:6876861 | Doi | 10.1016/j.celrep.2021.109490 |
| Citation | Lupse B, et al. (2021) Inhibition of PHLPP1/2 phosphatases rescues pancreatic beta-cells in diabetes. Cell Rep 36(5):109490 |
| abstractText | Pancreatic beta-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 beta-cell failure in diabetes. PHLPP levels are highly elevated in metabolically stressed human and rodent diabetic beta-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 beta-cell death. 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. Genetic inhibition of PHLPPs markedly improves beta-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 beta cells in diabetes. |
