PT  - JOURNAL ARTICLE
AU  - Yu-Te Yeh
AU  - Chandan Sona
AU  - Xin Yan
AU  - Adrija Pathak
AU  - Mark I. McDermott
AU  - Zhigang Xie
AU  - Liangwen Liu
AU  - Anoop Arunagiri
AU  - Yuting Wang
AU  - Amaury Cazenave-Gassiot
AU  - Adhideb Ghosh
AU  - Ferdinand von Meyenn
AU  - Sivarajan Kumarasamy
AU  - Sonia M. Najjar
AU  - Shiqi Jia
AU  - Markus R. Wenk
AU  - Alexis Traynor-Kaplan
AU  - Peter Arvan
AU  - Sebastian Barg
AU  - Vytas A. Bankaitis
AU  - Matthew N. Poy
TI  - Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction
AID  - 10.1101/2022.07.06.498991
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.07.06.498991
4099  - http://biorxiv.org/content/early/2022/07/06/2022.07.06.498991.short
4100  - http://biorxiv.org/content/early/2022/07/06/2022.07.06.498991.full
AB  - 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 decreased glucose-stimulated insulin secretion (GSIS) and reduced pancreatic beta-cell mass. Furthermore, PITPNA silencing in human islets confirmed its role in PtdIns-4-P synthesis and led 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 reversed these beta-cell defects and identify PITPNA as a critical target linked to beta-cell failure in T2D.Competing Interest StatementThe authors have declared no competing interest.