Regulation of Insulin Metabolism by Intermittent Hypoxia. Molecular Mechanisms

Intermittent hypoxia (IH) is the hallmark manifestation of sleep disordered breathing (SDB) with recurrent apnea. A large body of clinical evidence suggests that SDB patients are at increased risk to develop Type II diabetes. However, molecular mechanism(s) underlying the effects of IH on pancreatic beta cell function have not been established. Hypoxia‐inducible factor 1 (HIF‐1) mediates many of the systemic and cellular responses to IH. Mice with partial deficiency of HIF‐1α ( Hif1a +/‐ ) exhibit a remarkable absence of IH‐induced hypertension and breathing abnormalities, suggesting that activation of HIF‐1 contributes to the autonomic morbidities associated with IH. In the present study, we tested the role of HIF‐1α in IH‐induced pancreatic beta cell dysfunction. Experiments were performed on male littermate wild type (WT) and Hif1a +/‐ mice exposed to either 30 days of IH or normoxia. HIF‐1α levels were elevated in pancreatic islets from IH‐exposed WT mice but not in Hif1a +/‐ littermates. IH‐exposed WT mice exhibited elevated fasting plasma insulin levels and impaired glucose stimulated insulin secretion, but these effects were either absent or attenuated in IH‐ exposed Hif1a +/‐ mice. Furthermore, IH augmented basal insulin secretion and this effect was prevented by treating islets from WT mice with either digoxin or YC‐1, which blocked HIF‐1α accumulation. These results suggest that HIF‐1 mediates IH‐induced pancreatic beta cell dysfunction. Supported by NIH‐HL‐090554