Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction
Y.-T. Yeh, C. Sona, X. Yan, A. Pathak, M. I. McDermott, Z. Xie, L. Liu, A. Arunagiri, Y. Wang, A. Cazenave-Gassiot, A. Ghosh, F. von Meyenn, S. Kumarasamy, S. M. Najjar, S. Jia, M. R. Wenk, A. Traynor-Kaplan, P. Arvan, S. Barg, V. Bankaitis, M. N. Poy
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 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.
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