title: Effects of prolonged exposure to hypobaric hypoxia on oxidative stress, inflammation and gluco-insular regulation: the not-so-sweet price for good regulation.
abstract: OBJECTIVE
  The mechanisms by which low oxygen availability are associated with the development of insulin resistance remain obscure. We thus investigated the relationship between such gluco-insular derangements in response to sustained (hypobaric) hypoxemia, and changes in biomarkers of oxidative stress, inflammation and counter-regulatory hormone responses.
  
  
  METHODS
  After baseline testing in London (75 m), 24 subjects ascended from Kathmandu (1,300 m) to Everest Base Camp (EBC;5,300 m) over 13 days. Of these, 14 ascended higher, with 8 reaching the summit (8,848 m). Assessments were conducted at baseline, during ascent to EBC, and 1, 6 and 8 week(s) thereafter. Changes in body weight and indices of gluco-insular control were measured (glucose, insulin, C-Peptide, homeostasis model assessment of insulin resistance [HOMA-IR]) along with biomarkers of oxidative stress (4-hydroxy-2-nonenal-HNE), inflammation (Interleukin-6 [IL-6]) and counter-regulatory hormones (glucagon, adrenalin, noradrenalin). In addition, peripheral oxygen saturation (SpO2) and venous blood lactate concentrations were determined.
  
  
  RESULTS
  SpO2 fell significantly from 98.0% at sea level to 82.0% on arrival at 5,300 m. Whilst glucose levels remained stable, insulin and C-Peptide concentrations increased by >200% during the last 2 weeks. Increases in fasting insulin, HOMA-IR and glucagon correlated with increases in markers of oxidative stress (4-HNE) and inflammation (IL-6). Lactate levels progressively increased during ascent and remained significantly elevated until week 8. Subjects lost on average 7.3 kg in body weight.
  
  
  CONCLUSIONS
  Sustained hypoxemia is associated with insulin resistance, whose magnitude correlates with the degree of oxidative stress and inflammation. The role of 4-HNE and IL-6 as key players in modifying the association between sustained hypoxia and insulin resistance merits further investigation.
authors.affiliation: Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle on Tyne, United Kingdom.
authors.forename: Mario
authors.initials: M
authors.lastname: Siervo
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Riley
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, United Kingdom; University of Southampton, Clinical & Experimental Sciences, Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Bernadette O
authors.initials: BO
authors.lastname: Fernandez
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, United Kingdom.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Leckstrom
authors.affiliation: Centre for Altitude Space and Extreme Environment Medicine, Portex Unit, UCL Institute of Child Health, London, United Kingdom; Division of Surgery and Interventional Science, University College London, Royal Free Hospital, London, United Kingdom.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Martin
authors.affiliation: Centre for Altitude Space and Extreme Environment Medicine, Portex Unit, UCL Institute of Child Health, London, United Kingdom; University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Kay
authors.initials: K
authors.lastname: Mitchell
authors.affiliation: Centre for Altitude Space and Extreme Environment Medicine, Portex Unit, UCL Institute of Child Health, London, United Kingdom; University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom; Southampton NIHR Respiratory Biomedical Research Unit, Southampton, United Kingdom.
authors.forename: Denny Z H
authors.initials: DZ
authors.lastname: Levett
authors.affiliation: Centre for Altitude Space and Extreme Environment Medicine, Portex Unit, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Hugh E
authors.initials: HE
authors.lastname: Montgomery
authors.affiliation: Centre for Altitude Space and Extreme Environment Medicine, Portex Unit, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Monty G
authors.initials: MG
authors.lastname: Mythen
authors.affiliation: University of Southampton, Clinical & Experimental Sciences, Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom; Centre for Altitude Space and Extreme Environment Medicine, Portex Unit, UCL Institute of Child Health, London, United Kingdom; University Hospital Southampton NHS Foundation Trust, Southampton General Hospital, Southampton, United Kingdom; Southampton NIHR Respiratory Biomedical Research Unit, Southampton, United Kingdom.
authors.forename: Michael P W
authors.initials: MP
authors.lastname: Grocott
authors.affiliation: Warwick Systems Biology Centre, University of Warwick, Coventry, United Kingdom; Warwick Medical School, University of Warwick, Coventry, United Kingdom; University of Southampton, Clinical & Experimental Sciences, Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom; Southampton NIHR Respiratory Biomedical Research Unit, Southampton, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Feelisch
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D003404:Creatinine / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D006728:Hormones / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000097:blood* / Q000473:pathology*; D007249:Inflammation / Q000097:blood* / Q000473:pathology*; D007328:Insulin / Q000097:blood*; D007773:Lactates / Q000097:blood; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D018384:Oxidative Stress; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D006728:Hormones; D007328:Insulin; D007773:Lactates; D003404:Creatinine
references.citation: J Appl Physiol (1985). 2001 Aug;91(2):623-31
references.pmid: 11457773
references.citation: J Physiol. 2003 Oct 1;552(Pt 1):253-64
references.pmid: 12878760
references.citation: Am J Respir Crit Care Med. 2004 Jun 1;169(11):1231-7
references.pmid: 15044204
references.citation: Int J Biometeorol. 1986 Sep;30(3):231-8
references.pmid: 3533792
references.citation: Nat Clin Pract Endocrinol Metab. 2008 Nov;4(11):619-26
references.pmid: 18838972
references.citation: BMJ. 1995 Feb 18;310(6977):446
references.pmid: 7873953
references.citation: Mol Cell Biol. 2009 Aug;29(16):4467-83
references.pmid: 19546236
references.citation: J Physiol. 1997 Oct 1;504 ( Pt 1):241-9
references.pmid: 9350634
references.citation: Endocr Rev. 1998 Oct;19(5):608-24
references.pmid: 9793760
references.citation: Respirology. 2013 Jan;18(1):140-6
references.pmid: 22988888
references.citation: Am J Physiol Endocrinol Metab. 2000 May;278(5):E759-68
references.pmid: 10780930
references.citation: Mol Cell Biol. 2009 Mar;29(6):1575-91
references.pmid: 19114551
references.citation: Diabetologia. 1985 Jul;28(7):412-9
references.pmid: 3899825
references.citation: Eur J Endocrinol. 2007 Dec;157(6):733-40
references.pmid: 18057380
references.citation: Curr Pharm Des. 2004;10(14):1611-26
references.pmid: 15134560
references.citation: Diabetes. 1971 Dec;20(12):834-8
references.pmid: 5120326
references.citation: Biochem Biophys Res Commun. 2006 May 5;343(2):591-6
references.pmid: 16554025
references.citation: Resuscitation. 2001 Jun;49(3):307-14
references.pmid: 11723998
references.citation: Best Pract Res Clin Endocrinol Metab. 2010 Oct;24(5):843-51
references.pmid: 21112030
references.citation: Eur J Appl Physiol Occup Physiol. 1991;62(4):286-91
references.pmid: 2044540
references.citation: Res Q Exerc Sport. 2010 Dec;81(4):472-7
references.pmid: 21268471
references.citation: High Alt Med Biol. 2005 Winter;6(4):301-10
references.pmid: 16351564
references.citation: Diabetes Metab Rev. 1986;2(3-4):331-45
references.pmid: 3527619
references.citation: J Appl Physiol (1985). 1988 Dec;65(6):2545-51
references.pmid: 3215854
references.citation: Horm Behav. 2003 Jan;43(1):2-15
references.pmid: 12614627
references.citation: Obesity (Silver Spring). 2010 Apr;18(4):675-81
references.pmid: 20134417
references.citation: Sci Rep. 2011;1:109
references.pmid: 22355626
references.citation: Diabetes. 1984 May;33(5):486-94
references.pmid: 6373457
references.citation: Acta Physiol (Oxf). 2013 Sep;209(1):77-89
references.pmid: 23692825
references.citation: J Appl Physiol (1985). 2009 May;106(5):1538-44
references.pmid: 19265062
references.citation: Exp Physiol. 2013 Sep;98(9):1376-85
references.pmid: 23709585
references.citation: Acta Physiol (Oxf). 2008 Jan;192(1):37-48
references.pmid: 18171428
references.citation: Respir Physiol Neurobiol. 2007 Sep 30;158(2-3):128-31
references.pmid: 17482529
references.citation: Physiol Rev. 2008 Oct;88(4):1379-406
references.pmid: 18923185
references.citation: J Appl Physiol (1985). 1989 Mar;66(3):1430-5
references.pmid: 2651390
references.citation: Vitam Horm. 2009;80:613-33
references.pmid: 19251052
references.citation: PLoS One. 2013 May 29;8(5):e65400
references.pmid: 23734252
references.citation: Physiol Rev. 2013 Jan;93(1):1-21
references.pmid: 23303904
references.citation: BMC Med Res Methodol. 2010 Oct 21;10:98
references.pmid: 20964858
references.citation: Am J Respir Cell Mol Biol. 1999 Dec;21(6):710-8
references.pmid: 10572068
references.citation: Am J Physiol Cell Physiol. 2011 Mar;300(3):C385-93
references.pmid: 21123733
references.citation: Adv Exp Med Biol. 2003;536:559-64
references.pmid: 14635713
references.citation: Metabolism. 2010 Feb;59(2):200-5
references.pmid: 19765784
references.citation: Annu Rev Cell Dev Biol. 1999;15:551-78
references.pmid: 10611972
references.citation: J Clin Endocrinol Metab. 2012 Apr;97(4):E546-55
references.pmid: 22278428
references.citation: Diabetes Metab Res Rev. 2011 Jan;27(1):94-101
references.pmid: 21218513
references.citation: Nat Rev Drug Discov. 2010 Feb;9(2):107-15
references.pmid: 20118961
references.citation: Cytokine. 2000 Mar;12(3):246-52
references.pmid: 10704252
references.citation: Biochim Biophys Acta. 2010 Mar;1801(3):338-49
references.pmid: 20056169