Islet-Resident Macrophages as Dynamic Immunometabolic Integrators of β-Cell Fate in Health and Diabetes

Islet-resident macrophages (IRMs) have emerged as important regulators of pancreatic islet biology, operating at the intersection of metabolism and immunity. Beyond their classical roles as immune sentinels, accumulating evidence indicates that IRMs dynamically integrate β-cell activity, environmental cues, and metabolic stress, thereby coordinating islet homeostasis, adaptive remodelling, and disease progression. However, their context-dependent functions and therapeutic potential remain incompletely understood.

This review summarizes current evidence regarding IRM origins, phenotype, metabolic plasticity, and bidirectional crosstalk with β cells in health, type 1 diabetes, and type 2 diabetes. We further review emerging therapeutic concepts targeting macrophage metabolism, intercellular communication, and organelle function, while discussing current challenges in translating findings from murine IRMs to human disease.

Under physiological conditions, IRMs maintain islet integrity through surveillance, efferocytosis, trophic signalling, redox control, and maintenance of intercellular communication within the islet niche. In diabetes, chronic glucolipotoxicity, autoimmunity, oxidative stress, and amyloid-associated injury can redirect these homeostatic programs toward maladaptive inflammatory states that impair insulin secretion and accelerate β-cell loss. Collectively, these findings support a unified framework in which IRMs act as immunometabolic hubs integrating local and systemic signals to determine β-cell fate.

IRMs represent central immunometabolic hubs that orchestrate β-cell fate during health and diabetes. Emerging therapeutic strategies targeting macrophage metabolism, intercellular communication, and organelle function may help prioritize future mechanistic studies and guide safer macrophage-centered interventions for diabetes.