Hypoxia impairs blood glucose homeostasis in naked mole-rat subordinate adults but not queens.

Naked mole-rats (NMRs) are among the most hypoxia-tolerant mammals and metabolize only carbohydrates in hypoxia. Glucose is the primary building block of dietary carbohydrates but how blood glucose is regulated during hypoxia has not been explored in NMRs. We hypothesized that NMRs mobilize glucose stores to support anaerobic energy metabolism in hypoxia. To test this, we treated newborn, juvenile, and adult (subordinate and queen) NMRs in normoxia (21% O2) or hypoxia (7, 5, or 3% O2), while measuring metabolic rate, body temperature and blood [glucose]. We also challenged animals with glucose, insulin, or insulin-like growth factor-1 (IGF-1) injections and measured the rate of glucose clearance in normoxia and hypoxia. We found that: 1) blood [glucose] increases in moderate hypoxia in queens and pups but only in severe hypoxia in subordinate adults and juveniles; 2) glucose tolerance is similar between developmental stages in normoxia, but glucose clearance times are 2-3-fold longer in juveniles and subordinates than in queens or pups in hypoxia; 3) reoxygenation accelerates glucose clearance in hypoxic subordinate adults. Mechanistically, 4) insulin and IGF-1 reduce blood [glucose] in subordinates in both normoxia but only IGF-1 impacts blood [glucose] in hypoxic queens. Our results indicate that insulin signalling is impaired by hypoxia in NMRs, but queens utilize IGF-1 to overcome this limitation and effectively regulate blood glucose in hypoxia. This indicates that sexual maturation impacts blood glucose handling in hypoxic NMR queens, which may allow queens to spend longer periods of time in hypoxic nest chambers.