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

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 von Meyenn, Sivarajan Kumarasamy, Sonia M. Najjar, Shiqi Jia, Markus R. Wenk, Alexis Traynor-Kaplan, Peter Arvan, Sebastian Barg, Vytas A. Bankaitis and Matthew N. Poy ()
Additional contact information
Yu-Te Yeh: Johns Hopkins University, All Children’s Hospital
Chandan Sona: Johns Hopkins University, All Children’s Hospital
Xin Yan: University Medical Center Rostock
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
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
Sonia M. Najjar: Ohio University
Shiqi Jia: The First Affiliated Hospital of Jinan University
Markus R. Wenk: National University of Singapore
Alexis Traynor-Kaplan: University of Washington School of Medicine
Peter Arvan: University of Michigan Medical School
Sebastian Barg: Uppsala University
Vytas A. Bankaitis: Texas A&M University
Matthew N. Poy: Johns Hopkins University, All Children’s Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39978-1

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