>

Atf4 Protects Islet β-Cell Identity and Function Under Acute Glucose-Induced Stress but Promotes β-Cell Failure in the Presence of Free Fatty Acid

Authors

Yagan M Mahircan , Najam S Sadia , Hu R Ruiying , Wang Y Yu , Dickerson MT Mathew T , Dadi PK Prasanna K , Xu Y Yanwen , Simmons AJ Alan J , Stein R Roland , Adams CM Christopher M , Jacobson DA David A , Lau KS Ken S , Liu Q Qi , Gu G Guoqiang .
Diabetes. 2025 ; 74(5).
838-849

Abstract

Glucolipotoxicity, caused by combined hyperglycemia and hyperlipidemia, results in β-cell failure and type 2 diabetes via cellular stress-related mechanisms. Activating transcription factor 4 (Atf4) is an essential effector of stress response. We show here that Atf4 expression in β-cells is minimally required for glucose homeostasis in juvenile and adolescent mice but it is needed for β-cell function during aging and under obesity-related metabolic stress. Henceforth, Atf4-deficient β-cells older than 2 months after birth display compromised secretory function under acute hyperglycemia. In contrast, they are resistant to acute free fatty acid-induced dysfunction and reduced production of several factors essential for β-cell identity. Atf4-deficient β-cells downregulate genes involved in protein translation. They also upregulate several lipid metabolism or signaling genes, likely contributing to their resistance to free fatty acid-induced dysfunction. These results suggest that Atf4 activation is required for β-cell identity and function under high glucose. But Atf4 activation paradoxically induces β-cell failure in high levels of free fatty acids. Different transcriptional targets of Atf4 could be manipulated to protect β-cells from metabolic stress-induced failure.