TY - JOUR
T1 - Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction
AU - Yeh, Yu Te
AU - Sona, Chandan
AU - Yan, Xin
AU - Li, Yunxiao
AU - Pathak, Adrija
AU - McDermott, Mark I.
AU - Xie, Zhigang
AU - Liu, Liangwen
AU - Arunagiri, Anoop
AU - Wang, Yuting
AU - Cazenave-Gassiot, Amaury
AU - Ghosh, Adhideb
AU - von Meyenn, Ferdinand
AU - Kumarasamy, Sivarajan
AU - Najjar, Sonia M.
AU - Jia, Shiqi
AU - Wenk, Markus R.
AU - Traynor-Kaplan, Alexis
AU - Arvan, Peter
AU - Barg, Sebastian
AU - Bankaitis, Vytas A.
AU - Poy, Matthew N.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
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 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.
UR - http://www.scopus.com/inward/record.url?scp=85165001258&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-39978-1
DO - 10.1038/s41467-023-39978-1
M3 - Article
C2 - 37460527
AN - SCOPUS:85165001258
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4250
ER -