The Role Of CRHR1in High-altitude Hypoxia-induced Suppression Of Insulin Release

With the progress of society, technology and economy, more and more people travel to high altitudes for tourism, living and working. High-altitude hypoxia, however, induces several debilitating and discomfort and potentially high-altitude illnesses. Therefore, the relations between high-altitude and health, high-altitude and disease were more and moreThere are increasing researches about high-altitude, which not only induces acute mountain sickness (AMS), but effects blood glucose and insulin secretion, and causes metabolic and endocrine dysfunction. We previously showed that hypoxia results in increased corticotropin releasing hormone (CRH) in the paraventricular nucleus of hypothalamus.5,000m altitude hypoxia for5days induced the low plasma insulin mediated by CRH receptor1(CRHR1) in rats. However, the mechanism was not completely clear. CRH is the key.regulator of the hypothalamic-pituitary-adrenal (HP A) axis and is activated by a variety of stressors including hypoxia, and mediates neural and endocrine response to stress. Recent studies showed that CRHR1exists in human, mouse, and rat islets and CRH, through CRHR1, stimulates insulin secretion in a glucose-dependent manner. Here, we investigate about the involvement of CRHR1in hypoxia-suppressed insulin release.In this study, therefore, we used a rat model of hypobaric hypoxia, the cultured rat islets in vitro and a human trial with rapid ascent to the Tibet plateau to clarify the role of CRHR1in high-altitude hypoxia-induced suppression of insulin release. We found that hypobaric hypoxia of5,000m altitude for8h enhanced CRH, corticosterone (CORT), and glucose level in rat plasma, while decreased plasma insulin. Treatment with the CRHR1antagonist blocked the increase of glucose and CORT and the decrease of insulin in plasma. Both acute (8h) and subacute (5days) hypoxia of5,000m induced high lactate/pyruvate and AMP/ATP, and low ATP/ADP ratio in rat pancreas. These suggested that islets were in a lower oxygen supply and ATP deficient condition under hypoxia expostion. In islets cultured under normoxia, CRH stimulated insulin release in a glucose-and CRH-level dependent manner via the CRHR1initiating c AMP-protein kinase A pathway and calcium influx through L-type channels. However, the insulinotropic effect of CRH was inactivated although Crhrl mRNA was upregulated in cultured islets under hypoxia (5%O2). The same inactivation was shown under rotenone induced ATP deficient condition. Rotenone dose-dependently inhibited insulin release, and1nM rotenone induced ATP deficiency could block the1nM CRH-induced insulinotropic action. CRH stimulated high cAMP and ATP/ADP ratio in islets was also abolished by rotenone induced ATP deficiency. CRH enhanced calcium oscillation in islet β cells was exterminated under ATP deficiency. These suggested that the insulinotropic effect of CRH depends on sufficient oxygen and ATP supplement, and may be inactivated due to hypoxia reduced cellular ATP, cAMP, and calcium influx.Hypoxia increased not only plasma CRH but CORT by activating the HPA axis in rats. In isolated rat islets, Dexamethasone (DEX) inhibited insulin secretion under normoxia and5%O2hypoxia. Under rotenone induced ATP deficient condition, DEX still could decrease insulin release, which negatively correlated with DEX and ATP concentration. DEX elevated Serum and glucocorticoid-inducible kinase1(Sgkl) mRNA and inhibited Glucose transporter2(Glut2) and Crhrl mRNA expression under normoxia, and these changes were not affected by ATP-deficiency or hypoxia. In vivo, treatment with the glucocorticoid receptor (GR) antagonist reversed the hypoxia-induced hyperglycemia and low plasma insulin in rats. Immunofluorescence showed a higher SGK1in islet β-cells under hypoxia, and this was also blocked by GR antagonist. So we proposed that CRH induced high CORT under hypoxia decreased plasma insulin via activated SGK1in islets, which is another mechanism of inhibited insulin release under hypoxia.The data shows decreased blood oxygen saturation, elevated plasma CRH and no changed insulin level in the volunteers rapidly ascended to3,680m altitude. Plasma glucose increased while insulin sensitivity decreased only in volunteers with AMS, and the increases of plasma glucose were correlated with AMS. Plasma cortisol was decreased by taking Rhodiola rosea, but high plasma CRH level is still evoked by hypoxia. Under these conditions, the raised plasma CRH level failed to stimulate insulin release during high-altitude hypoxia.In conclusion, hypoxia may attenuate the CRH-insulinotropic effect by reducing cellular ATP, cAMP, and calcium influx. The inhibition of insulin release under hypoxia is associated with high CORT upregulated SGK1in rats. In humans, high-altitude hypoxia enhances plasma CRH but not change in insulin; however, reduced insulin sensitivity and elevated blood glucose occurs only in AMS volunteers having high plasma CRH. In this paper we addressed the mechanism of high-altitude hypoxia suppressed insulin release, which induced by the inactivation of CRH-insulinotropic effect and the inhibition of glucocorticoid on insulin release. And we proposed a dynamic changeable regulation of CRH-insulinotropic role in islets, which depends on O2and ATP availability. This study suggested a new perspective of insulin secretion under hypoxia.