Pdgfrα deficiency in islet β-cells up-regulates apoptosis of beta-cells and disturbs glucose metabolism in B6 mice

Zhang, Luyao, Xing, Yanpeng, Wang, Pai, Gu, Jianlei, Peng, Jian, Huang, Juan, Pearson, James Alexander ORCID: https://orcid.org/0000-0002-2867-2269, Hu, Youjia, Zhao, Hongyu, Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845 and Wen, Li 2025. Pdgfrα deficiency in islet β-cells up-regulates apoptosis of beta-cells and disturbs glucose metabolism in B6 mice. Frontiers in Endocrinology 16 , 1630979. 10.3389/fendo.2025.1630979

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Abstract

Introduction: Pancreatic β-cell dysfunction is a key contributor to the development of Type 2 Diabetes. The platelet-derived growth factor receptor α (PDGFRα) is known to play a crucial role in β-cell proliferation and expansion. However, its specific role in β-cell function and glucose metabolism remains unclear. This study aimed to investigate the effects of Pdgfrα deficiency on islet β-cell function and overall glucose metabolism. Methods: To explore this, we generated β-cell-specific Pdgfrα-deficient C57BL/6 mice (Pdgfrafl/fl Pdx1-cre+) and assessed their metabolic function under both normal and high-fat diet conditions. Various parameters were measured, including body weight, body fat composition, glucose metabolism, insulin content, and β-cell apoptosis. Additionally, we conducted mechanistic analyses to understand the signaling pathways involved. Results: Pdgfrα-deficient mice exhibited significantly greater weight gain and increased body fat compared to controls. These mice also showed impaired glucose metabolism, reduced insulin content in β-cells, and increased β-cell apoptosis. Mechanistic studies revealed that Pdgfrα deletion led to suppression of Atf5 expression via downregulation of the PI3K pathway. This suppression resulted in enhanced β-cell apoptosis. Furthermore, Atf5 was found to regulate the expression of Gadd45b, Bcl2, and aminoacyl-tRNA synthetases, which are involved in insulin biosynthesis and glucose metabolism. Discussion: Our findings demonstrate that PDGFRα plays a critical role in maintaining β-cell function and glucose homeostasis. Loss of PDGFRα impairs β-cell survival and insulin production, likely through the PI3K–Atf5 axis. These insights suggest that targeting β-cell apoptotic pathways, particularly involving Atf5 and its downstream effectors, may offer promising avenues for the prevention and treatment of Type 2 Diabetes.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Frontiers Media
ISSN:	1664-2392
Date of First Compliant Deposit:	3 November 2025
Date of Acceptance:	3 August 2025
Last Modified:	03 Nov 2025 14:15
URI:	https://orca.cardiff.ac.uk/id/eprint/182066

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