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| Item Type: | Article |
|---|---|
| Title: | Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction |
| Creators Name: | Yeh, Y.T., Sona, C., Yan, X., Li, Y., Pathak, A., McDermott, M.I., Xie, Z., Liu, L., Arunagiri, A., Wang, Y., Cazenave-Gassiot, A., Ghosh, A., von Meyenn, F., Kumarasamy, S., Najjar, S.M., Jia, S., Wenk, M.R., Traynor-Kaplan, A., Arvan, P., Barg, S., Bankaitis, V.A. and Poy, M.N. |
| 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, 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. |
| Keywords: | Phospholipids, Type 2 Diabetes, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 14 |
| Number: | 1 |
| Page Range: | 4250 |
| Date: | 17 July 2023 |
| Official Publication: | https://doi.org/10.1038/s41467-023-39978-1 |
| PubMed: | View item in PubMed |
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