PHLPP1/2 phosphatases as new target for beta-cell-directed therapy in diabetes
Final Report Abstract
Both type 1 diabetes (T1D) and type 2 diabetes (T2D) result from an absolute or relative decline in pancreatic β-cell function and/or mass. There is a critical need to develop therapeutic approaches to restore and maintain β-cell mass in patients with diabetes. Apoptosis as well as impaired function of insulin producing β-cell are hallmarks of β-cell failure and the fundamental cause of diabetes. Modulation of beta-cell apoptosis and/or enhancement of beta-cell regenerative capacity therefore represent an attractive therapeutic approach to the treatment of diabetes. Serine-threonine phosphatases (STPs) such as PHLPP1/2 (PH domain leucine-rich repeat protein phosphatase-1/2) regulate cell death and serve as potential targets for drug development. Here, we identify (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.
Publications
- Reciprocal regulation of mTOR complexes in pancreatic islets from humans with type 2 diabetes. Diabetologia, 2017, Apr;60(4):668-678
Yuan,T, Rafizadeh,S, Gorrepati,KDD, Lupse,B, Oberholzer,J, Maedler,K, & Ardestani, A
(See online at https://doi.org/10.1007/s00125-016-4188-9) - Hippo Signaling: Key Emerging Pathway in Cellular and Whole-Body Metabolism. Trends in Endocrinology & Metabolism, 2018, Jul;29(7):492-509
Ardestani, A, Lupse, B & Maedler, K
(See online at https://doi.org/10.1016/j.tem.2018.04.006) - mTORC1 Signaling: A Double Edge Sword in Diabetic β-cells. Cell Metabolism, 2018, Feb 6;27(2):314-331
Ardestani, A, Lupse,B, Yoshiaki,K, Leibowitz,G, & Maedler, K
(See online at https://doi.org/10.1016/j.cmet.2017.11.004) - mTORC2 Signaling: A Path for Pancreatic β-Cell’s growth and function. J Mol Biol. 2018 Mar 30;430(7):904-918
Yuan, T, Lupse, B, Maedler, K & Ardestani, A
(See online at https://doi.org/10.1016/j.jmb.2018.02.013) - The Hippo signaling pathway in pancreatic β-cells: functions and regulations. Endocrine Review, 2018, Feb 1;39(1):21-35
Ardestani, A & Maedler, K
(See online at https://doi.org/10.1210/er.2017-00167) - Neratinib Protects Pancreatic Beta Cells in Diabetes. Nature Communications, 2019, Nov 1;10(1):5015
Ardestani,A, Li,S, Annamalai,K, Lupse,B, …, Tremblay,MS, Shen,W & Maedler, K
(See online at https://doi.org/10.1038/s41467-019-12880-5) - Inhibition of PHLPP1/2 phosphatases rescues pancreatic β-cells in diabetes. Cell Reports, 2021 Aug 3;36(5):109490
Lupse,B, Annamalai,K, Ibrahim, H, …, Maedler,K, & Ardestani, A
(See online at https://doi.org/10.1016/j.celrep.2021.109490) - The Hippo kinase LATS2 impairs pancreatic β-cell survival in diabetes through the mTORC1-autophagy axis. Nature Communications, 2021 Aug 13;12(1):4928
Yuan,T, Annamalai,K, Naik,S, …, Maedler,K, & Ardestani, A
(See online at https://doi.org/10.1038/s41467-021-25145-x) - PHLPP1 deletion restores pancreatic β-cell survival and normoglycemia in the db/db mouse model of obesity-associated diabetes. Cell Death & Discovery, 2022 Feb 8;8(1):57
Lupse,B, Heise,N, Maedler,K, & Ardestani, A
(See online at https://doi.org/10.1038/s41420-022-00853-5)
