IGF-mediated glucose signalling is retained in adult naked mole-rats.

Environmental hypoxia imposes severe constraints on aerobic metabolism, yet the naked mole-rat (Heterocephalus glaber) achieves remarkable resilience against low oxygen stress through profound metabolic suppression and substrate flexibility. To investigate the molecular basis of glucose regulation under low oxygen, we examined the insulin and insulin-like growth factor (IGF) signaling pathways across developmental stages and social castes. Juvenile, subordinate adult, and queen NMRs were exposed to 1 h of normoxia (21% O₂) or acute hypoxia (3% O₂), and tissues were analyzed for the expression of igf1, igf2, insr, and glucose/fructose transporters (glut1, glut4, glut5) at both gene and protein levels. Hypoxia markedly suppressed igf1, igf2, and insr expression in the brain of juveniles and subordinates (50–90% reduction), while promoting glut1 upregulation in heart and kidney, suggesting tissue-specific preservation of glucose uptake capacity in energetically critical organs. In contrast, queens exhibited a pronounced downregulation of glut4 and glut5 expression in muscle and liver, indicating reduced glucose and fructose utilization. These findings reveal that metabolic regulation under hypoxia is modulated not only by oxygen availability but also by social hierarchy and physiological role. Subordinates and juveniles maintain glucose transport to sustain activity during acute hypoxia, whereas queens employ a more energy-conserving phenotype aligned with their sedentary reproductive function. Collectively, this study provides the first evidence that IGF-mediated glucose signaling in NMRs operates in a caste- and tissue-specific manner, offering mechanistic insight into how social structure and metabolic flexibility jointly support survival under extreme hypoxic stress.