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

Lupse, Blaz; Annamalai, Karthika; Ibrahim, Hazem; Kaur, Supreet; Geravandi, Shirin; Sarma, Bhavishya; Pal, Anasua; Awal, Sushil; Joshi, Arundhati; Rafizadeh, Sahar; Madduri, Murali Krishna; Khazaei, Mona; Liu, Huan; Yuan, Ting; He, Wei; Gorrepati, Kanaka Durga Devi; Azizi, Zahra; Qi, Qi; Ye, Keqiang; Oberholzer, Jose; Maedler, Kathrin; Ardestani, Amin

Authors

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



Abstract

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.

Citation

Lupse, B., Annamalai, K., Ibrahim, H., Kaur, S., Geravandi, S., Sarma, B., …Ardestani, A. (2021). Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes. Cell reports, 36(5), Article 109490. https://doi.org/10.1016/j.celrep.2021.109490

Journal Article Type Article
Acceptance Date Jul 14, 2021
Online Publication Date Aug 3, 2021
Publication Date Aug 3, 2021
Deposit Date Jan 4, 2024
Publicly Available Date Jan 8, 2024
Journal Cell Reports
Print ISSN 2211-1247
Electronic ISSN 2211-1247
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 36
Issue 5
Article Number 109490
DOI https://doi.org/10.1016/j.celrep.2021.109490
Keywords Beta cell; Type 2 diabetes; T2D; Pleckstrin homology domain leucine-rich repeat protein phosphatases 1 and 2; PHLPP1/2; Apoptosis; MST1; AKT; MTORC1; Insulin
Public URL https://hull-repository.worktribe.com/output/4461543

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