Inactivation of corticotropin-releasing hormone-induced insulinotropic role by high-altitude hypoxia

Ke Hao, Fan-Ping Kong, Yu-Qi Gao, Jia-Wei Tang, Jian Chen, A Mark Evans, Stafford L Lightman, Xue-Qun Chen, Ji-Zeng Du

Research output: Contribution to journalArticle (Academic Journal)peer-review

14 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)785-95
Number of pages11
JournalDiabetes
Volume64
Issue number3
DOIs
Publication statusPublished - Mar 2015

Bibliographical note

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Keywords

  • Adenosine Triphosphate/metabolism
  • Adolescent
  • Adult
  • Altitude
  • Animals
  • Blood Glucose/drug effects
  • Calcium/metabolism
  • Corticosterone/blood
  • Corticotropin-Releasing Hormone/blood
  • Cyclic AMP
  • Humans
  • Hydrocortisone/blood
  • Hypoxia/blood
  • Insulin/blood
  • Male
  • Pancreas/metabolism
  • Pyrimidines/pharmacology
  • Pyrroles/pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors
  • Young Adult

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