Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes.

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. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Blaz Lupse, Karthika Annamalai, Hazem Ibrahim, Supreet Kaur, Shirin Geravandi, Bhavishya Sarma, Anasua Pal, Sushil Awal, Arundhati Joshi, Sahar Rafizadeh, Murali Krishna Madduri, Mona Khazaei, Huan Liu, Ting Yuan, Wei He, Kanaka Durga Devi Gorrepati, Zahra Azizi, Qi Qi, Keqiang Ye, Jose Oberholzer, Kathrin Maedler, Amin Ardestani. Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes. Cell reports. 2021 Aug 03;36(5):109490

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PMID: 34348155

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