title: Insulin resistance is associated with tissue-specific regulation of HIF-1α and HIF-2α during mild chronic intermittent hypoxia.
abstract: Chronic intermittent hypoxia (CIH) is a feature of obstructive sleep apnea (OSA). Whereas clinical studies have demonstrated the association between OSA and insulin resistance, the molecular mechanisms behind it are still unknown. Herein we investigated the effect of mild CIH on insulin sensitivity and we evaluated the changes in insulin and HIF signaling pathways that occur in CIH-induced insulin resistance. We showed that mild CIH obtained by 5/6 hypoxic (5%O2) cycles/h, 10.5h/day during 28 and 35 days increased arterial blood pressure. Insulin resistance and insulinemia increased with CIH duration, being significantly different after 35 days of CIH. Thirty-five days of CIH decreased insulin receptor expression and phosphorylation in skeletal muscle and adipose tissue, but not in the liver. Conversely, Glut2 expression increased in the liver of CIH-animals. Thirty-five days of CIH up-regulated HIF-1α in the liver and down-regulated HIF-1α and HIF-2α in skeletal muscle. We concluded that the effect of CIH on insulin sensitivity and signaling is time-dependent and is associated with changes in HIF signaling in insulin-sensitive tissues.
authors.affiliation: CEDOC, Centro Estudos Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: J F
authors.initials: JF
authors.lastname: Sacramento
authors.affiliation: CEDOC, Centro Estudos Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: M J
authors.initials: MJ
authors.lastname: Ribeiro
authors.affiliation: Laboratório de Fisiologia, IBILI, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: T
authors.initials: T
authors.lastname: Rodrigues
authors.affiliation: CEDOC, Centro Estudos Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal; UIS-Unidade de Investigação em Saúde, Escola Superior de Saúde de Leiria, Instituto Politécnico de Leiria, Leiria, Portugal.
authors.forename: M P
authors.initials: MP
authors.lastname: Guarino
authors.affiliation: CEDOC, Centro Estudos Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: L N
authors.initials: LN
authors.lastname: Diogo
authors.affiliation: Laboratório de Fisiologia, IBILI, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal.
authors.forename: R
authors.initials: R
authors.lastname: Seiça
authors.affiliation: CEDOC, Centro Estudos Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: E C
authors.initials: EC
authors.lastname: Monteiro
authors.affiliation: Laboratório de Fisiologia, IBILI, Faculdade de Medicina, Universidade de Coimbra, Coimbra, Portugal; Instituto Politécnico de Coimbra, Coimbra Health Shcool (ESTeSC), Department of Complementary Sciences, Coimbra, Portugal.
authors.forename: P
authors.initials: P
authors.lastname: Matafome
authors.affiliation: CEDOC, Centro Estudos Doenças Crónicas, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal. Electronic address: silvia.conde@fcm.unl.pt.
authors.forename: S V
authors.initials: SV
authors.lastname: Conde
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D062186:Arterial Pressure / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001835:Body Weight; D004195:Disease Models, Animal; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D010766:Phosphorylation; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000378:metabolism; D020181:Sleep Apnea, Obstructive / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051273:Glucose Transporter Type 2; D051275:Glucose Transporter Type 4; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007328:Insulin; D008055:Lipids; D011972:Receptor, Insulin; D000099162:Endothelial PAS Domain-Containing Protein 1; C497444:Hif1a protein, rat; C495683:Slc2a2 protein, rat; C495694:Slc2a4 protein, rat
keywords: Chronic intermittent hypoxia; Insulin resistance; Insulin signaling and HIF signaling; Obstructive sleep apnea