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

## TL;DR

Removing PDGFRα in insulin-producing cells of mice leads to cell death and worsened blood sugar control, suggesting a new target for diabetes treatment.

## Contribution

This study reveals a novel role of PDGFRα in β-cell survival and glucose metabolism via the PI3K–Atf5 signaling pathway.

## Key findings

- Pdgfrα deficiency in β-cells increases apoptosis and reduces insulin content.
- Loss of PDGFRα impairs glucose metabolism and increases body fat in mice.
- PDGFRα deletion suppresses Atf5 via PI3K, affecting insulin biosynthesis and cell survival.

## Abstract

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.

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.

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.

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.