{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T21:41:57Z","timestamp":1780522917385,"version":"3.54.1"},"reference-count":74,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2019,8,26]],"date-time":"2019-08-26T00:00:00Z","timestamp":1566777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Obstructive sleep apnea (OSA) causes many systemic disorders via mechanisms related to sympathetic nerve activation, systemic inflammation, and oxidative stress. OSA typically shows repeated sleep apnea followed by hyperventilation, which results in intermittent hypoxia (IH). IH is associated with an increase in sympathetic activity, which is a well-known pathophysiological mechanism in hypertension and insulin resistance. In this review, we show the basic and clinical significance of IH from the viewpoint of not only systemic regulatory mechanisms focusing on pulmonary circulation, but also cellular mechanisms causing lifestyle-related diseases. First, we demonstrate how IH influences pulmonary circulation to cause pulmonary hypertension during sleep in association with sleep state-specific change in OSA. We also clarify how nocturnal IH activates circulating monocytes to accelerate the infiltration ability to vascular wall in OSA. Finally, the effects of IH on insulin secretion and insulin resistance are elucidated by using an in vitro chamber system that can mimic and manipulate IH. The obtained data implies that glucose-induced insulin secretion (GIS) in pancreatic \u03b2 cells is significantly attenuated by IH, and that IH increases selenoprotein P, which is one of the hepatokines, as well as TNF-\u03b1, CCL-2, and resistin, members of adipokines, to induce insulin resistance via direct cellular mechanisms. Clinical and experimental findings concerning IH give us productive new knowledge of how lifestyle-related diseases and pulmonary hypertension develop during sleep.<\/jats:p>","DOI":"10.3390\/ijerph16173101","type":"journal-article","created":{"date-parts":[[2019,8,26]],"date-time":"2019-08-26T10:54:53Z","timestamp":1566816893000},"page":"3101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Effects of Intermittent Hypoxia on Pulmonary Vascular and Systemic Diseases"],"prefix":"10.3390","volume":"16","author":[{"given":"Hiroshi","family":"Kimura","sequence":"first","affiliation":[{"name":"Department of Advanced Medicine for Pulmonary Circulation and Respiratory Failure, Graduate School of Medicine, Nippon Medical School, Bunkyo, Tokyo 113-8603, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyo","family":"Ota","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Nara Medical University, Kashihara, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Kimura","sequence":"additional","affiliation":[{"name":"Center for Pulmonary Diseases, NHO Tokyo National Hospital, Kiyose, Tokyo 204-0023, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4066-0199","authenticated-orcid":false,"given":"Shin","family":"Takasawa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Nara Medical University, Kashihara, Nara 634-8521, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.smrv.2016.07.002","article-title":"Prevalence of obstructive sleep apnea in the general population: A systematic review","volume":"34","author":"Senaratna","year":"2017","journal-title":"Sleep Med. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1378\/chest.127.5.1674","article-title":"Oxidative stress in obstructive sleep apnea","volume":"127","author":"Yamauchi","year":"2005","journal-title":"Chest"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s11325-006-0074-x","article-title":"Evidence for activation of nuclear factor kappaB in obstructive sleep apnea","volume":"10","author":"Yamauchi","year":"2006","journal-title":"Sleep Breath."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1159\/000196328","article-title":"Differences in the response of genioglossal muscle activity to sustained hypoxia between healthy subjects and patients with obstructive sleep apnea","volume":"61","author":"Kimura","year":"1994","journal-title":"Respiration"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1164\/ajrccm\/139.1.164","article-title":"Abnormal breathing during sleep and chemical control of breathing during wakefulness in patients with sleep apnea syndrome","volume":"139","author":"Kunitomo","year":"1989","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1164\/ajrccm\/139.5.1198","article-title":"Progesterone therapy for sleep apnea syndrome evaluated by occlusion pressure responses to exogenous loading","volume":"139","author":"Kimura","year":"1989","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/jsr.12337","article-title":"Diaphragm and genioglossus corticomotor excitability in patients with obstructive sleep apnea and control subjects","volume":"25","author":"Borel","year":"2016","journal-title":"J. Sleep Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.5664\/jcsm.7318","article-title":"Obesity hyperventilation syndrome: Early detection to nocturnal-only hypercapnia in an obese population","volume":"14","author":"Sivam","year":"2018","journal-title":"J. Clin. Sleep Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1183\/09031936.00147712","article-title":"Functional impact of pulmonary hypertension due to hypoventilation and changes under noninvasive ventilation","volume":"43","author":"Held","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1378\/chest.07-0027","article-title":"Recent advances in obesity hypoventilation syndrome","volume":"132","author":"Mokhlesi","year":"2007","journal-title":"Chest"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"R1404","DOI":"10.1152\/ajpregu.1995.269.6.R1404","article-title":"Changes in efferent pulmonary sympathetic nerve activity during systemic hypoxia in anesthetized cats","volume":"269","author":"Shirai","year":"1995","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1007\/s00395-014-0432-y","article-title":"Pulmonary vascular tone is dependent on the central modulation of sympathetic nerve activity following chronic intermittent hypoxia","volume":"109","author":"Shirai","year":"2014","journal-title":"Basic Res. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"R785","DOI":"10.1152\/ajpregu.00363.2011","article-title":"Chronic intermittent hypoxia alters glutamatergic control of sympathetic and respiratory activities in the commissural NTS of rats","volume":"302","author":"Zoccal","year":"2012","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.1164\/ajrccm.159.6.9808064","article-title":"Manifestation of pulmonary hypertension during REM sleep in obstructive sleep apnea syndrome","volume":"159","author":"Niijima","year":"1999","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1161\/01.HYP.0000147893.08533.d8","article-title":"Sympathetic neural activation in nondiabetic metabolic syndrome and its further augmentation by hypertension","volume":"44","author":"Huggett","year":"2004","journal-title":"Hypertension"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101","DOI":"10.3389\/fphys.2017.00101","article-title":"Muscle sympathetic nerve activity is associated with liver insulin sensitivity in obese non-diabetic men","volume":"8","author":"Chen","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"H497","DOI":"10.1152\/ajpheart.00217.2017","article-title":"Vascular endothelial function masks increased sympathetic vasopressor activity in rats with metabolic syndrome","volume":"314","author":"Battault","year":"2018","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1136\/thx.2005.057745","article-title":"Prevalance of obstructive sleep apnoea in men with type 2 diabetes","volume":"61","author":"West","year":"2006","journal-title":"Thorax"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1093\/aje\/kwh261","article-title":"Sleep-disordered breathing, glucose intolerance, and insulin resistance: The Sleep Heart Health Study","volume":"160","author":"Punjabi","year":"2004","journal-title":"Am. J. Epidemiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1164\/ajrccm.165.5.2103001","article-title":"Obstructive sleep apnea is independently associated with insulin resistance","volume":"165","author":"Ip","year":"2002","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_21","first-page":"52","article-title":"Obesity, obstructive sleep apnea and type 2 diabetes mellitus: Epidemiology and pathophysiologic insights","volume":"2","author":"Jehan","year":"2018","journal-title":"Sleep Med. Disord."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1177\/1479972314552806","article-title":"Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome","volume":"11","author":"Seetho","year":"2014","journal-title":"Chron. Respir. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1183\/09031936.00151110","article-title":"Metabolic syndrome, insulin resistance and sleepiness in real-life obstructive sleep apnoea","volume":"39","author":"Bonsignore","year":"2012","journal-title":"Eur. Respir. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.2337\/db12-1463","article-title":"Carotid body denervation prevents the development of insulin resistance and hypertension induced by hypercaloric diets","volume":"62","author":"Ribeiro","year":"2013","journal-title":"Diabetes"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1164\/ajrccm.163.1.2001008","article-title":"Sleep-disordered breathing and cardiovascular disease: Cross-sectional results of the Sleep Heart Health Study","volume":"163","author":"Shahar","year":"2001","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"369","DOI":"10.5551\/jat.3319","article-title":"Nocturnal intermittent hypoxia and metabolic syndrome; the effect of being overweight: The CIRCS study","volume":"17","author":"Muraki","year":"2010","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.smrv.2014.06.003","article-title":"Does obstructive sleep apnea cause endothelial dysfunction? A critical review of the literature","volume":"20","author":"Hoyos","year":"2015","journal-title":"Sleep Med. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1074\/jbc.M115.686709","article-title":"Hypoxia potentiates palmitate-induced pro-inflammatory activation of primary human macrophages","volume":"291","author":"Snodgrass","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1161\/HYPERTENSIONAHA.115.05886","article-title":"Endothelial hypoxia-inducible factor-1\u03b1 promotes atherosclerosis and monocyte recruitment by upregulating microRNA-19a","volume":"66","author":"Akhtar","year":"2015","journal-title":"Hypertension"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1089\/ars.2007.1946","article-title":"Oxidative stress in obstructive sleep apnea: Putative pathways to the cardiovascular complications","volume":"10","author":"Yamauchi","year":"2008","journal-title":"Antioxid. Redox Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1093\/sleep\/27.1.129","article-title":"Obstructive sleep apnea and carotid-artery intima-media thickness","volume":"27","author":"Suzuki","year":"2004","journal-title":"Sleep"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1111\/j.1440-1843.2009.01540.x","article-title":"Nocturnal hypoxic stress activates invasive ability of monocytes in patients with obstructive sleep apnoea syndrome","volume":"14","author":"Tamaki","year":"2009","journal-title":"Respirology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1093\/hmg\/ddp504","article-title":"Life course variations in the associations between FTO and MC4R gene variants and body size","volume":"19","author":"Hardy","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00125-009-1616-0","article-title":"Nocturnal intermittent hypoxia and the development of type 2 diabetes: The Circulatory Risk in Communities Study (CIRCS)","volume":"53","author":"Muraki","year":"2010","journal-title":"Diabetologia"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.sleep.2016.05.009","article-title":"Obstructive sleep apnea and incident type 2 diabetes","volume":"25","author":"Nagayoshi","year":"2016","journal-title":"Sleep Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"609","DOI":"10.5664\/jcsm.4768","article-title":"Nocturnal hypoxemia and severe obstructive sleep apnea are associated with incident type 2 diabetes in a population cohort of men","volume":"11","author":"Appleton","year":"2015","journal-title":"J. Clin. Sleep Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.lfs.2011.11.011","article-title":"Attenuation of glucose-induced insulin secretion by intermittent hypoxia via down-regulation of CD38","volume":"30","author":"Ota","year":"2012","journal-title":"Life Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"S462","DOI":"10.2337\/diabetes.51.2007.S462","article-title":"Recent advances in the Okamoto model: The CD38-cyclic ADP-ribose signal system and the regenerating gene protein (Reg)-Reg receptor system in \u03b2-cells","volume":"51","author":"Okamoto","year":"2002","journal-title":"Diabetes"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.biocel.2017.07.009","article-title":"From insulin synthesis to secretion: Alternative splicing of type 2 ryanodine receptor gene is essential for insulin secretion in pancreatic \u03b2 cells","volume":"91","author":"Okamoto","year":"2017","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1517\/14728222.2016.1123691","article-title":"Regenerating gene (REG) product and its potential clinical usage","volume":"20","author":"Takasawa","year":"2016","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2988","DOI":"10.1016\/j.bbamcr.2013.08.004","article-title":"Prevention of Reg I-induced \u03b2-cell apoptosis by IL-6\/dexamethasone through activation of HGF gene regulation","volume":"1833","author":"Nakagawa","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/j.lfs.2013.09.001","article-title":"Pancreatic \u03b2 cell proliferation by intermittent hypoxia via up-regulation of Reg family genes and HGF gene","volume":"93","author":"Ota","year":"2013","journal-title":"Life Sci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1172\/JCI1656","article-title":"Autoantibodies against CD38 (ADP-ribosyl cyclase\/cyclic ADP-ribose hydrolase) that impair glucose-induced insulin secretion in insulin-dependent diabetes patients","volume":"102","author":"Ikehata","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1007\/s001250051026","article-title":"A missense mutation in CD38 gene, a novel factor for insulin secretion: Association with Type II diabetes mellitus in Japanese subjects and evidence of abnormal function when expressed in vitro","volume":"41","author":"Yagui","year":"1998","journal-title":"Diabetologia"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2309","DOI":"10.2337\/diabetes.48.12.2309","article-title":"Autoantibodies to CD38 (ADP-ribosyl cyclase\/cyclic ADP-ribose hydrolase) in Caucasian patients with diabetes: Effects on insulin release from human islets","volume":"48","author":"Pupilli","year":"1999","journal-title":"Diabetes"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1111\/j.1365-2362.2004.01419.x","article-title":"Autoantibodies to REG. a beta-cell regeneration factor, in diabetic patients","volume":"34","author":"Shervani","year":"2004","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1046\/j.1365-2249.2001.01683.x","article-title":"Anti-CD38 autoimmunity in patients with chronic autoimmune thyroiditis or Graves\u2019 disease","volume":"126","author":"Antonelli","year":"2001","journal-title":"Clin. Exp. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.cyto.2013.02.023","article-title":"Increased CD38 expression in T cells and circulating anti-CD38 IgG autoantibodies differentially correlate with distinct cytokine profiles and disease activity in systemic lupus erythematosus patients","volume":"62","author":"Zumaquero","year":"2013","journal-title":"Cytokine"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/cei.12142","article-title":"Involvement of autoimmunity to REG, a regenerating factor, in patients with primary Sj\u00f6gren\u2019s syndrome","volume":"174","author":"Yoshimoto","year":"2013","journal-title":"Clin. Exp. Immunol."},{"key":"ref_50","first-page":"130","article-title":"Up-regulation of selenoprotein P and HIP\/PAP mRNAs in hepatocytes by intermittent hypoxia via down-regulation of miR-203","volume":"11","author":"Uchiyama","year":"2017","journal-title":"Biochem. Biophys. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.cmet.2010.09.015","article-title":"A liver-derived secretory protein, selenoprotein P, causes insulin resistance","volume":"12","author":"Misu","year":"2010","journal-title":"Cell Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1002\/hep.20845","article-title":"HIP\/PAP accelerates liver regeneration and protects against acetoaminophen injury in mice","volume":"42","author":"Lieu","year":"2005","journal-title":"Hepatology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1111\/jdi.12823","article-title":"Sleep apnea and type 2 diabetes","volume":"9","author":"Muraki","year":"2018","journal-title":"J. Diabetes Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"651","DOI":"10.3389\/fendo.2018.00651","article-title":"Increased level of angiopoietin like proteins 4 and 8 in people with sleep apnea","volume":"9","author":"AlKhairi","year":"2018","journal-title":"Front. Endocrinol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Uchiyama, T., Itaya-Hironaka, A., Yamauchi, A., Makino, M., Sakuramoto-Tsuchida, S., Shobatake, R., Ota, H., Takeda, M., Ohbayashi, C., and Takasawa, S. (2019). Intermittent hypoxia up-regulates CCL2, RETN, and TNF\u03b1 mRNAs in adipocytes via down-regulation of mR-452. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20081960"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1378\/chest.09-0360","article-title":"Interactions between obesity and obstructive sleep apnea: Implications for treatment","volume":"137","author":"Caples","year":"2010","journal-title":"Chest"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/sbr.12078","article-title":"Metabolic dysfunction in obstructive sleep apnea: A critical examination of underlying mechanisms","volume":"13","author":"Mesarwi","year":"2015","journal-title":"Sleep Biol. Rhythms"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1689","DOI":"10.1097\/00005537-200010000-00022","article-title":"Obstructive sleep apnea syndrome: A comparison between Far-East Asian and white men","volume":"110","author":"Li","year":"2000","journal-title":"Laryngoscope"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.biocel.2017.12.012","article-title":"Up-regulation of POMC and CART mRNAs by intermittent hypoxia via GATA transcription factors in human neuronal cells","volume":"95","author":"Shobatake","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_60","first-page":"137","article-title":"Brain-gut axis and the role in the control of food intake","volume":"55","author":"Konturek","year":"2004","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Shobatake, R., Itaya-Hironaka, A., Yamauchi, A., Makino, M., Sakuramoto-Tsuchida, S., Uchiyama, T., Ota, H., Takahashi, N., Ueno, S., and Sugie, K. (2019). Intermittent hypoxia up-regulates gene expressions of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and neurotensin (NTS) in enteroendocrine cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20081849"},{"key":"ref_62","unstructured":"WHO (2014). Attaining the Nine Global Noncommunicable Diseases Targets; A Shared Responsicility, World Health Organization. Global Status Report on Noncommunicable Diseases."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.2337\/dc12-0336","article-title":"Metabolic syndrome and risk of cancer: A systematic review and meta-analysis","volume":"35","author":"Esposito","year":"2012","journal-title":"Diabetes Care"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1056\/NEJMoa021423","article-title":"Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults","volume":"348","author":"Calle","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ecl.2013.09.009","article-title":"Metabolic syndrome","volume":"43","author":"Samson","year":"2014","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1164\/rccm.200610-1527OC","article-title":"Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity","volume":"175","author":"Iiyori","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1002\/dmrr.1156","article-title":"Acute hypoxia and exercise improve insulin sensitivity (S(I) (2*)) in individuals with type 2 diabetes","volume":"27","author":"Mackenzie","year":"2011","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e197","DOI":"10.2337\/dc13-1350","article-title":"Ten nights of moderate hypoxia improves insulin sensitivity in obese humans","volume":"36","author":"Lecoultre","year":"2013","journal-title":"Diabetes Care"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.cytogfr.2016.10.003","article-title":"Myokines and adipokines: Involvement in the crosstalk between skeletal muscle and adipose tissue","volume":"33","author":"Li","year":"2017","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1378\/chest.07-2544","article-title":"Independent association between obstructive sleep apnea and subclinical coronary artery disease","volume":"133","author":"Sorajja","year":"2008","journal-title":"Chest"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s41105-018-0145-y","article-title":"Examining the association between obstructive sleep apnea and cardiometabolic risk factors in the elderly","volume":"16","author":"Wu","year":"2018","journal-title":"Sleep Biol. Rhythms"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3042","DOI":"10.1016\/j.yexcr.2013.08.014","article-title":"Intermittent hypoxia induces the proliferation of rat vascular smooth muscle cell with the increases in epidermal growth factor family and erbB2 receptor","volume":"319","author":"Kyotani","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1002\/2211-5463.12430","article-title":"Intermittent hypoxia-induced epiregulin expression by IL-6 production in human coronary artery smooth muscle cells","volume":"8","author":"Kyotani","year":"2018","journal-title":"FEBS Open Bio"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Kyotani, Y., Takasawa, S., and Yoshizumi, M. (2019). Proliferative pathways of vascular smooth muscle cells by intermittent hypoxia. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112706"}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/16\/17\/3101\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:14:08Z","timestamp":1760188448000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/16\/17\/3101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,26]]},"references-count":74,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["ijerph16173101"],"URL":"https:\/\/doi.org\/10.3390\/ijerph16173101","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,26]]}}}