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Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction

Author

Listed:
  • Yu-Te Yeh

    (Johns Hopkins University, All Children’s Hospital
    Johns Hopkins University, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism)

  • Chandan Sona

    (Johns Hopkins University, All Children’s Hospital
    Johns Hopkins University, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism)

  • Xin Yan

    (University Medical Center Rostock
    Max Delbrück Center for Molecular Medicine)

  • Yunxiao Li

    (University Medical Center Rostock)

  • Adrija Pathak

    (Texas A&M University)

  • Mark I. McDermott

    (Texas A&M Health Science Center)

  • Zhigang Xie

    (Texas A&M Health Science Center)

  • Liangwen Liu

    (Uppsala University)

  • Anoop Arunagiri

    (University of Michigan Medical School)

  • Yuting Wang

    (Max Delbrück Center for Molecular Medicine)

  • Amaury Cazenave-Gassiot

    (National University of Singapore
    National University of Singapore)

  • Adhideb Ghosh

    (Laboratory of Nutrition and Metabolic Epigenetics, Department of Health Sciences and Technology)

  • Ferdinand von Meyenn

    (Laboratory of Nutrition and Metabolic Epigenetics, Department of Health Sciences and Technology)

  • Sivarajan Kumarasamy

    (Ohio University
    Ohio University)

  • Sonia M. Najjar

    (Ohio University
    Ohio University)

  • Shiqi Jia

    (The First Affiliated Hospital of Jinan University)

  • Markus R. Wenk

    (National University of Singapore
    National University of Singapore)

  • Alexis Traynor-Kaplan

    (University of Washington School of Medicine
    ATK Analytics, Innovation and Discovery, LLC)

  • Peter Arvan

    (University of Michigan Medical School)

  • Sebastian Barg

    (Uppsala University)

  • Vytas A. Bankaitis

    (Texas A&M University
    Texas A&M Health Science Center
    Texas A&M University)

  • Matthew N. Poy

    (Johns Hopkins University, All Children’s Hospital
    Johns Hopkins University, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism
    Max Delbrück Center for Molecular Medicine)

Abstract

Defects in insulin processing and granule maturation are linked to pancreatic beta-cell failure during type 2 diabetes (T2D). Phosphatidylinositol transfer protein alpha (PITPNA) stimulates activity of phosphatidylinositol (PtdIns) 4-OH kinase to produce sufficient PtdIns-4-phosphate (PtdIns-4-P) in the trans-Golgi network to promote insulin granule maturation. PITPNA in beta-cells of T2D human subjects is markedly reduced suggesting its depletion accompanies beta-cell dysfunction. Conditional deletion of Pitpna in the beta-cells of Ins-Cre, Pitpnaflox/flox mice leads to hyperglycemia resulting from decreasing glucose-stimulated insulin secretion (GSIS) and reducing pancreatic beta-cell mass. Furthermore, PITPNA silencing in human islets confirms its role in PtdIns-4-P synthesis and leads to impaired insulin granule maturation and docking, GSIS, and proinsulin processing with evidence of ER stress. Restoration of PITPNA in islets of T2D human subjects reverses these beta-cell defects and identify PITPNA as a critical target linked to beta-cell failure in T2D.

Suggested Citation

  • Yu-Te Yeh & Chandan Sona & Xin Yan & Yunxiao Li & Adrija Pathak & Mark I. McDermott & Zhigang Xie & Liangwen Liu & Anoop Arunagiri & Yuting Wang & Amaury Cazenave-Gassiot & Adhideb Ghosh & Ferdinand v, 2023. "Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39978-1
    DOI: 10.1038/s41467-023-39978-1
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    1. Elizabeth Haythorne & Maria Rohm & Martijn Bunt & Melissa F. Brereton & Andrei I. Tarasov & Thomas S. Blacker & Gregor Sachse & Mariana Silva dos Santos & Raul Terron Exposito & Simon Davis & Otto Bab, 2019. "Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    2. Rudy Behnia & Sean Munro, 2005. "Organelle identity and the signposts for membrane traffic," Nature, Nature, vol. 438(7068), pages 597-604, December.
    3. Gilbert Di Paolo & Pietro De Camilli, 2006. "Phosphoinositides in cell regulation and membrane dynamics," Nature, Nature, vol. 443(7112), pages 651-657, October.
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