title: Inactivation of corticotropin-releasing hormone-induced insulinotropic role by high-altitude hypoxia.
abstract: We have shown that hypoxia reduces plasma insulin, which correlates with corticotropin-releasing hormone (CRH) receptor 1 (CRHR1) in rats, but the mechanism remains unclear. Here, we report that hypobaric hypoxia at an altitude of 5,000 m for 8 h enhances rat plasma CRH, corticosterone, and glucose levels, whereas the plasma insulin and pancreatic ATP/ADP ratio is reduced. In islets cultured under normoxia, CRH stimulated insulin release in a glucose- and CRH-level-dependent manner by activating CRHR1 and thus the cAMP-dependent protein kinase pathway and calcium influx through L-type channels. In islets cultured under hypoxia, however, the insulinotropic effect of CRH was inactivated due to reduced ATP and cAMP and coincident loss of intracellular calcium oscillations. Serum and glucocorticoid-inducible kinase 1 (SGK1) also played an inhibitory role. In human volunteers rapidly ascended to 3,860 m, plasma CRH and glucose levels increased without a detectable change in plasma insulin. By contrast, volunteers with acute mountain sickness (AMS) exhibited a marked decrease in HOMA insulin sensitivity (HOMA-IS) and enhanced plasma CRH. In conclusion, hypoxia may attenuate the CRH-insulinotropic effect by reducing cellular ATP/ADP ratio, cAMP and calcium influx, and upregulated SGK1. Hypoxia may not affect HOMA-IS in healthy volunteers but reduces it in AMS volunteers.
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, China.
authors.forename: Fan-Ping
authors.initials: FP
authors.lastname: Kong
authors.affiliation: Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Yu-Qi
authors.initials: YQ
authors.lastname: Gao
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, China.
authors.forename: Jia-Wei
authors.initials: JW
authors.lastname: Tang
authors.affiliation: Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Third Military Medical University, Chongqing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Chen
authors.affiliation: Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, U.K.
authors.forename: A Mark
authors.initials: AM
authors.lastname: Evans
authors.affiliation: Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, U.K.
authors.forename: Stafford L
authors.initials: SL
authors.lastname: Lightman
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, China dujz@zju.edu.cn chewyg@zju.edu.cn.
authors.forename: Xue-Qun
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, Zhejiang University, Hangzhou, China dujz@zju.edu.cn chewyg@zju.edu.cn.
authors.forename: Ji-Zeng
authors.initials: JZ
authors.lastname: Du
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000531:Altitude; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology*; D000242:Cyclic AMP; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D000860:Hypoxia / Q000097:blood* / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008297:Male; D010179:Pancreas / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D055815:Young Adult; D000099052:CRF Receptor, Type 1
chemical_list: D001786:Blood Glucose; C101628:CP 154526; D007328:Insulin; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D000255:Adenosine Triphosphate; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D002118:Calcium; D003345:Corticosterone; D006854:Hydrocortisone