Poster Presentation The International Congress of Neuroendocrinology 2014

 Inactivation of corticotropin releasing hormone-induced insulinotropic role by high-altitude hypoxia (#238)

Ke Hao 1 , Yu-Qi Gao 2 , Jia-Wei Tang 1 , Jian Chen 2 , Fan-Ping Kong 1 , Mark Evans 3 , Stafford Lightman 4 , Xue-Qun Chen 1 , Ji-Zeng Du 1
  1. Department of Basic Medical Sciences,School of Medicine, Zhejiang University, Hangzhou, China
  2. Department of Pathophysiology and High Altitude Physiology, Third Military Medical University, Chongqing, China
  3. Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
  4. the Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, UK

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 of 5,000 m altitude for 8 h enhanced rat plasma CRH, corticosterone, and glucose levels, while plasma insulin and pancreatic ATP content were 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-protein kinase A 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. In this respect serum and glucocorticoid-inducible kinase 1 (SGK1) also played an inhibitory role. In human volunteers rapidly ascended to 3,680 m, plasma CRH and glucose increased without a detectable change in plasma insulin. By contrast, volunteers with acute mountain sickness (AMS) exhibited a marked decrease in insulin sensitivity and enhanced plasma CRH. In conclusion, hypoxia may attenuate the CRH-insulinotropic effect by reducing cellular ATP, cAMP, and calcium influx and upregulated SGK1. Hypoxia may not affect insulin sensitivity in healthy volunteers, but reduces it in AMS volunteers.

This work was supported by grants from the Ministry of Science and Technology of China, the National Basic Research Program of China (973 Program No. 2012CB518200 and No. 2006CB504100) and the Foundation of Ministry of Health of China (No. 201002012).