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

• Published in: Nature communications Vol. 14; no. 1; pp. 4250 - 19
• Main Authors: Yeh, Yu-Te, Sona, Chandan, Yan, Xin, Li, Yunxiao, Pathak, Adrija, McDermott, Mark I., Xie, Zhigang, Liu, Liangwen, Arunagiri, Anoop, Wang, Yuting, Cazenave-Gassiot, Amaury, Ghosh, Adhideb, von Meyenn, Ferdinand, Kumarasamy, Sivarajan, Najjar, Sonia M., Jia, Shiqi, Wenk, Markus R., Traynor-Kaplan, Alexis, Arvan, Peter, Barg, Sebastian, Bankaitis, Vytas A., Poy, Matthew N.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.07.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 14/28; 38/39; 631/443/319/1642/137/773; 631/45/287/1194; 64/110; 692/163/2743/137/773; 82/29; 82/51; 82/58; Animals; Beta cells; Clonal deletion; Defects; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Exocytosis; Failure; Flox; Glucose - metabolism; Golgi apparatus; Granular materials; Human subjects; Humanities and Social Sciences; Humans; Hyperglycemia; Insulin; Insulin - metabolism; Insulin secretion; Insulin-Secreting Cells - metabolism; Islets of Langerhans - metabolism; Kinases; Maturation; Mice; multidisciplinary; Pancreas; Phosphatidylinositol transfer protein; Proinsulin - metabolism; Proteins; Restoration; Science; Science (multidisciplinary); Synthesis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39978-1

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 , Pitpna flox/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. Type 2 diabetes (T2D) is characterized by pancreatic beta-cell failure. Here, the authors show restoration of Phosphatidylinositol transfer protein alpha (PITPNA), a mediator of PtdIns-4-phosphate synthesis in the trans-Golgi network, in human T2D islets reverses impaired insulin granule maturation, exocytosis, and ER stress.