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Tau suppresses microtubule-regulated pancreatic insulin secretion

Molecular Psychiatry volume 28, pages 3982–3993 (2023)Cite this article

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Abstract

Tau protein is implicated in the pathogenesis of Alzheimer’s disease (AD) and other tauopathies, but its physiological function is in debate. Mostly explored in the brain, tau is also expressed in the pancreas. We further explored the mechanism of tau’s involvement in the regulation of glucose-stimulated insulin secretion (GSIS) in islet β-cells, and established a potential relationship between type 2 diabetes mellitus (T2DM) and AD. We demonstrate that pancreatic tau is crucial for insulin secretion regulation and glucose homeostasis. Tau levels were found to be elevated in β-islet cells of patients with T2DM, and loss of tau enhanced insulin secretion in cell lines, drosophila, and mice. Pharmacological or genetic suppression of tau in the db/db diabetic mouse model normalized glucose levels by promoting insulin secretion and was recapitulated by pharmacological inhibition of microtubule assembly. Clinical studies further showed that serum tau protein was positively correlated with blood glucose levels in healthy controls, which was lost in AD. These findings present tau as a common therapeutic target between AD and T2DM.

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Fig. 1: Pancreatic tau protein levels were elevated in Type 2 diabetes.
Fig. 2: Tau suppression enhances insulin release.
Fig. 3: Knockdown of tau in INS-1 cells increases insulin secretion.
Fig. 4: Microtubule disassembly promotes insulin release.
Fig. 5: Tau protein inhibits insulin release in islet cells by promoting microtubule assembly.
Fig. 6: Serum tau level is positively correlated with blood glucose levels physiologically and disrupted by EOAD pathology.

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Acknowledgements

This work is dedicated to the memory of Dr. Huaxi Xu, who passed away while this paper was being prepared. Huaxi critically reviewed the manuscript. We thank Dr. Linda Partridge (Max Planck Institute for Biology of Ageing) for the kind gift of the dTauKO line, and thank all organ donors and their families for their generosity and for enabling this work. Thanks to the staff of St Vincent’s Institute involved in the islet isolation program and Donatelife for obtaining research consent and providing the Human Pancreata. We also thank Dr. Shuting Zhang for helping with the EOAD sample collection. This work was supported by the National Key Research and Development Project of China (2021YFC2500100), the National Natural Science Foundation of China (81722016, 82071191), the program of the National Clinical Research Center for Geriatrics of West China Hospital (Z2021LC001), the Australian National Health & Medical Research Council (NHMRC), and the Alzheimer’s Australia Dementia Research Foundation. The Florey Institute of Neuroscience and Mental Health and the St. Vincent’s Institute acknowledge support from the Victorian Government, in particular, funding from the Operational Infrastructure Support Grant.

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  1. These authors contributed equally: Salvatore P. Mangiafico, Qing-Zhang Tuo, Xiao-Lan Li.

Authors and Affiliations

  1. Department of Medicine, Austin Hospital, University of Melbourne, Heidelberg, VIC, 3084, Australia

    Salvatore P. Mangiafico, Christian Haralambous, Chieh-Hsin Yang, Christos N. Joannides, Benjamin J. Lamont & Sofianos Andrikopoulos

  2. Department of Neurology and State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan Province, 610041, China

    Qing-Zhang Tuo, Xiao-Lan Li, Yu Liu, Xu-Long Ding, Qing Wang, Xiang Zhang, Lunzhi Dai, Hai-Huai He, Biao Dong & Peng Lei

  3. Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, 30 Royal Parade, Parkville, VIC, 3052, Australia

    Scott Ayton, Ashley I. Bush & Peng Lei

  4. Diabetes and Metabolism Division, Garvan Institute of Medical Research, St Vincent’s Hospital, Sydney, NSW, 2010, Australia

    D. Ross Laybutt & Jeng Yie Chan

  5. St. Vincent’s Institute of Medical Research and Department of Medicine, St. Vincent’s Hospital, The University of Melbourne, Fitzroy, VIC, 3065, Australia

    Cameron Kos, Helen E. Thomas & Thomas Loudovaris

  6. Institute for Cellular Transplantation, Department of Surgery, College of Medicine, University of Arizona, Tucson, AZ, 85724-5066, USA

    Thomas Loudovaris

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Contributions

PL and SPM conceived the project; PL, AIB, and SA raised funds and supervised the overall project; XLL and QW collected clinical samples and performed the biomarker tests. SPM, QZT, XLL, SA, CNJ, BJL, QW, and DRL performed in vivo studies with supervision from PL, AIB, and SA; HET, CK, and TL provided human T2D samples and performed the staining; XLL, CH, JYC, and CHY performed in vitro studies with supervision from PL and SA; XZ performed in Drosophila studies with supervision from HHH; YL and XLD performed and analyzed protein mass spectrometry studies with supervision from LZD; XLL prepared CRISPR-related experiments with supervision from BD and PL; SPM, QZT, SA, AIB, and PL integrated the data and wrote the drafts of the manuscript; all authors edited the manuscript.

Corresponding authors

Correspondence to Sofianos Andrikopoulos, Ashley I. Bush or Peng Lei.

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Competing interests

AIB is a shareholder in Alterity Ltd, Cogstate Ltd, Eucalyptus Pty Ltd, and Mesoblast Ltd. He is a paid consultant for and has a profit share interest in, Collaborative Medicinal Development Pty Ltd. All other authors declare that they have no competing interests.

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Mangiafico, S.P., Tuo, QZ., Li, XL. et al. Tau suppresses microtubule-regulated pancreatic insulin secretion. Mol Psychiatry 28, 3982–3993 (2023). https://doi.org/10.1038/s41380-023-02267-w

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