Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction
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 (PtdIn...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-39978-1 |
| _version_ | 1827895007695077376 |
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| author | Yu-Te Yeh Chandan Sona Xin Yan Yunxiao Li Adrija Pathak Mark I. McDermott Zhigang Xie Liangwen Liu Anoop Arunagiri Yuting Wang Amaury Cazenave-Gassiot Adhideb Ghosh Ferdinand von Meyenn Sivarajan Kumarasamy Sonia M. Najjar Shiqi Jia Markus R. Wenk Alexis Traynor-Kaplan Peter Arvan Sebastian Barg Vytas A. Bankaitis Matthew N. Poy |
| author_facet | Yu-Te Yeh Chandan Sona Xin Yan Yunxiao Li Adrija Pathak Mark I. McDermott Zhigang Xie Liangwen Liu Anoop Arunagiri Yuting Wang Amaury Cazenave-Gassiot Adhideb Ghosh Ferdinand von Meyenn Sivarajan Kumarasamy Sonia M. Najjar Shiqi Jia Markus R. Wenk Alexis Traynor-Kaplan Peter Arvan Sebastian Barg Vytas A. Bankaitis Matthew N. Poy |
| author_sort | Yu-Te Yeh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T22:15:32Z |
| format | Article |
| id | doaj.art-07e41593908f4d84a89d335f3da86332 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-12T22:15:32Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-07e41593908f4d84a89d335f3da863322023-07-23T11:18:51ZengNature PortfolioNature Communications2041-17232023-07-0114111910.1038/s41467-023-39978-1Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunctionYu-Te Yeh0Chandan Sona1Xin Yan2Yunxiao Li3Adrija Pathak4Mark I. McDermott5Zhigang Xie6Liangwen Liu7Anoop Arunagiri8Yuting Wang9Amaury Cazenave-Gassiot10Adhideb Ghosh11Ferdinand von Meyenn12Sivarajan Kumarasamy13Sonia M. Najjar14Shiqi Jia15Markus R. Wenk16Alexis Traynor-Kaplan17Peter Arvan18Sebastian Barg19Vytas A. Bankaitis20Matthew N. Poy21Johns Hopkins University, All Children’s HospitalJohns Hopkins University, All Children’s HospitalTranslational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center RostockTranslational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center RostockDepartment of Biochemistry & Biophysics, Texas A&M UniversityDepartment of Cell Biology & Genetics, Texas A&M Health Science CenterDepartment of Cell Biology & Genetics, Texas A&M Health Science CenterMedical Cell Biology, Uppsala UniversityDivision of Metabolism, Endocrinology & Diabetes, University of Michigan Medical SchoolMax Delbrück Center for Molecular MedicineSingapore Lipidomics Incubator, Life Sciences Institute, National University of SingaporeLaboratory of Nutrition and Metabolic Epigenetics, Department of Health Sciences and TechnologyLaboratory of Nutrition and Metabolic Epigenetics, Department of Health Sciences and TechnologyDepartment of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio UniversityDepartment of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio UniversityThe First Affiliated Hospital of Jinan UniversitySingapore Lipidomics Incubator, Life Sciences Institute, National University of SingaporeDepartment of Medicine, University of Washington School of MedicineDivision of Metabolism, Endocrinology & Diabetes, University of Michigan Medical SchoolMedical Cell Biology, Uppsala UniversityDepartment of Biochemistry & Biophysics, Texas A&M UniversityJohns Hopkins University, All Children’s HospitalAbstract 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.https://doi.org/10.1038/s41467-023-39978-1 |
| spellingShingle | Yu-Te Yeh Chandan Sona Xin Yan Yunxiao Li Adrija Pathak Mark I. McDermott Zhigang Xie Liangwen Liu Anoop Arunagiri Yuting Wang Amaury Cazenave-Gassiot Adhideb Ghosh Ferdinand von Meyenn Sivarajan Kumarasamy Sonia M. Najjar Shiqi Jia Markus R. Wenk Alexis Traynor-Kaplan Peter Arvan Sebastian Barg Vytas A. Bankaitis Matthew N. Poy Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction Nature Communications |
| title | Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction |
| title_full | Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction |
| title_fullStr | Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction |
| title_full_unstemmed | Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction |
| title_short | Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction |
| title_sort | restoration of pitpna in type 2 diabetic human islets reverses pancreatic beta cell dysfunction |
| url | https://doi.org/10.1038/s41467-023-39978-1 |
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