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

Author:

Yeh Yu-Te,Sona Chandan,Yan Xin,Li Yunxiao,Pathak Adrija,McDermott Mark I.,Xie Zhigang,Liu Liangwen,Arunagiri AnoopORCID,Wang Yuting,Cazenave-Gassiot AmauryORCID,Ghosh AdhidebORCID,von Meyenn FerdinandORCID,Kumarasamy Sivarajan,Najjar Sonia M.,Jia ShiqiORCID,Wenk Markus R.,Traynor-Kaplan Alexis,Arvan PeterORCID,Barg SebastianORCID,Bankaitis Vytas A.ORCID,Poy Matthew N.ORCID

Abstract

AbstractDefects 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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

Helmholtz Association

European Foundation for the Study of Diabetes

Deutsche Forschungsgemeinschaft

Novo Nordisk Fonden

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. The expanding roles of PI4P and PI(4,5)P2 at the plasma membrane: Role of phosphatidylinositol transfer proteins;Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids;2024-03

2. Rescuing β cells;Science Signaling;2023-07-25

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