Restoration of PITPNA in Type 2 Diabetic Human Islets Reverses Pancreatic Beta-cell Dysfunction

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Jul 17

PMID 37460527

Authors

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

Affiliations

Soon will be listed here.

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 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.

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