EGFR ligands critically regulate beta cell mass, insulin secretion, and hepatic gluconeogenesis, bridging oncology and metabolic research.

The epidermal growth factor receptor (EGFR/ErbB1) is a well-established driver of cellular proliferation and differentiation, primarily recognized for its role in oncology. However, its contribution to glucose homeostasis has emerged as a significant, yet less understood, area of metabolic research. Current therapeutic strategies for metabolic disorders often lack comprehensive targets that address the multifaceted nature of glucose regulation, including beta cell function, insulin sensitivity, and hepatic glucose production. This review addresses the gap by synthesizing evidence on how EGFR ligands influence these critical metabolic processes, moving beyond the receptor's oncological focus.

This mini-review systematically synthesized current evidence from diverse in vitro mechanistic studies and preclinical rodent models to elucidate the role of the seven known EGFR ligands—EGF, TGFα, amphiregulin, HB-EGF, betacellulin, epiregulin, and epigen—in regulating glucose homeostasis. The authors critically evaluated their contributions to beta cell mass, insulin secretion, hepatic gluconeogenesis, and peripheral insulin sensitivity. Furthermore, the review examined the metabolic paradox associated with EGFR tyrosine kinase inhibitors (TKIs) and addressed safety considerations regarding the mitogenic potential inherent to these ligands, providing a roadmap for future translational research in the EGFR/ErbB metabolic signaling axis.

The review found compelling evidence from preclinical and in vitro studies demonstrating that the seven EGFR ligands collectively play significant roles in glucose homeostasis. Specifically, these ligands were shown to influence beta cell mass and proliferation, impacting the capacity for insulin production. They also modulate insulin secretion dynamics and contribute to the regulation of hepatic gluconeogenesis, a key process in glucose production.

Furthermore, the synthesis of evidence highlighted their involvement in improving peripheral insulin sensitivity, suggesting a broad impact across multiple metabolic tissues. The review also identified a metabolic paradox where EGFR TKIs, while effective in oncology, exhibit complex and sometimes contradictory effects on glucose metabolism. Structural innovations, such as chimeric ligands, were presented as emerging strategies to potentially harness the metabolic benefits of EGFR signaling while mitigating mitogenic risks, paving the way for targeted therapeutic development.