Obstructive sleep apnea (OSA) is associated with insulin resistance (IR) and glucose intolerance. Elevated endothelin-1 (ET-1) levels have been observed in OSA patients and in mice exposed to intermittent hypoxia (IH). We examined whether pharmacological blockade of type A and type B ET-1 receptors (ETA and ETB) would ameliorate glucose intolerance and IR in mice exposed to IH. Subcutaneously implanted pumps delivered BQ-123 (ETA antagonist; 200 nmol/kg/day), BQ-788 (ETB antagonist; 200 nmol/kg/day) or vehicle (saline or propyleneglycol [PG]) for 14 days in C57BL6/J mice (10/group). During treatment, mice were exposed to IH (decreasing the FiO2 from 20.9% to 6%, 60/h) or intermittent air (IA). After IH or IA exposure, insulin (0.5 IU/kg) or glucose (1 mg/kg) was injected intraperitoneally and plasma glucose determined after injection and area under glucose curve (AUC) was calculated. Fourteen-day IH increased fasting glucose levels (122 ± 7 vs. 157 ± 8 mg/dL, PG: 118 ± 6 vs. 139 ± 8; both p < 0.05) and impaired glucose tolerance (AUCglucose: 19,249 ± 1105 vs. 29,124 ± 1444, PG AUCglucose: 18,066 ± 947 vs. 25,135 ± 797; both p < 0.05) in vehicle-treated animals. IH-induced impairments in glucose tolerance were partially ameliorated with BQ-788 treatment (AUCglucose: 21,969 ± 662; p < 0.05). Fourteen-day IH also induced IR (AUCglucose: 7185 ± 401 vs. 8699 ± 401; p < 0.05). Treatment with BQ-788 decreased IR under IA (AUCglucose: 5281 ± 401, p < 0.05) and reduced worsening of IR with IH (AUCglucose: 7302 ± 401, p < 0.05). There was no effect of BQ-123 on IH-induced impairments in glucose tolerance or IR. Our results suggest that ET-1 plays a role in IH-induced impairments in glucose homeostasis.

Department for the Study of Obesity and Diabetes 3rd Faculty of Medicine Charles University Prague Czechia

Division of Pulmonary and Critical Care Medicine Johns Hopkins University Baltimore MD United States

Zobrazit více v PubMed

Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc (2008) 5:136–43.10.1513/pats.200709-155MG PubMed DOI PMC

Young T, Shahar E, Nieto FJ, Redline S, Newman AB, Gottlieb DJ, et al. Predictors of sleep-disordered breathing in community-dwelling adults: the sleep heart health study. Arch Intern Med (2002) 162:893–900.10.1001/archinte.162.8.893 PubMed DOI

Cano-Pumarega I, Duran-Cantolla J, Aizpuru F, Miranda-Serrano E, Rubio R, Martinez-Null C, et al. Obstructive sleep apnea and systemic hypertension: longitudinal study in the general population: the Vitoria sleep cohort 2. Am J Respir Crit Care Med (2011) 184:1299–304.10.1164/rccm.201101-0130OC PubMed DOI

Marin JM, Agusti A, Villar I, Forner M, Nieto D, Carrizo SJ, et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension 1. JAMA (2012) 307(20):2169–76.10.1001/jama.2012.3418 PubMed DOI PMC

Gottlieb DJ, Yenokyan G, Newman AB, O’Connor GT, Punjabi NM, Quan SF, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study 2. Circulation (2010) 122:352–60.10.1161/CIRCULATIONAHA.109.901801 PubMed DOI PMC

Redline S, Yenokyan G, Gottlieb DJ, Shahar E, O’Connor GT, Resnick HE, et al. Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med (2010) 182:269–77.10.1164/rccm.200911-1746OC PubMed DOI PMC

Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death 1. N Engl JMed (2005) 353:2034–41.10.1056/NEJMoa043104 PubMed DOI

Yeboah J, Redline S, Johnson C, Tracy R, Ouyang P, Blumenthal RS, et al. Association between sleep apnea, snoring, incident cardiovascular events and all-cause mortality in an adult population: MESA 1. Atherosclerosis (2011) 219(2):963–8.10.1016/j.atherosclerosis.2011.08.021 PubMed DOI PMC

Young T, Finn L, Peppard PE, Szklo-Coxe M, Austin D, Nieto FJ, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep (2008) 31:1071–8.10.5665/sleep/31.8.1071 PubMed DOI PMC

Punjabi NM, Caffo BS, Goodwin JL, Gottlieb DJ, Newman AB, O’Connor GT, et al. Sleep-disordered breathing and mortality: a prospective cohort study 2. PLoS Med (2009) 6:e1000132.10.1371/journal.pmed.1000132 PubMed DOI PMC

Marshall NS, Wong KK, Liu PY, Cullen SR, Knuiman MW, Grunstein RR. Sleep apnea as an independent risk factor for all-cause mortality: the Busselton health study. Sleep (2008) 31:1079–85.10.5665/sleep/31.8.1079 PubMed DOI PMC

Punjabi NM, Shahar E, Redline S, Gottlieb DJ, Givelber R, Resnick HE. Sleep heart health study investigators. Am J Epidemiol (2004) 160:521–30.10.1093/aje/kwh261 PubMed DOI

Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR, Smith PL. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men 1. Am J Respir Crit Care Med (2002) 165:677–82.10.1164/ajrccm.165.5.2104087 PubMed DOI

Reichmuth KJ, Austin D, Skatrud JB, Young T. Association of sleep apnea and type II diabetes: a population-based study. Am J Respir Crit Care Med (2005) 172(12):1590–5.10.1164/rccm.200504-637OC PubMed DOI PMC

Carreras A, Kayali F, Zhang J, Hirotsu C, Wang Y, Gozal D. Metabolic effects of intermittent hypoxia in mice: steady versus high-frequency applied hypoxia daily during the rest period. Am J Physiol Regul Integr Comp Physiol (2012) 303:R700–9.10.1152/ajpregu.00258.2012 PubMed DOI PMC

Fenik VB, Singletary T, Branconi JL, Davies RO, Kubin L. Glucoregulatory consequences and cardiorespiratory parameters in rats exposed to chronic-intermittent hypoxia: effects of the duration of exposure and losartan 2. Front Neurol (2012) 3:51.10.3389/fneur.2012.00051 PubMed DOI PMC

Iiyori N, Alonso LC, Li J, Sanders MH, Garcia-Ocana A, O’Doherty RM, et al. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med (2007) 175:851–7.10.1164/rccm.200610-1527OC PubMed DOI PMC

Lee EJ, Alonso LC, Stefanovski D, Strollo HC, Romano LC, Zou B, et al. Time-dependent changes in glucose and insulin regulation during intermittent hypoxia and continuous hypoxia 1. Eur J Appl Physiol (2013) 113:467–78.10.1007/s00421-012-2452-3 PubMed DOI PMC

Polotsky VY, Li J, Punjabi NM, Rubin AE, Smith PL, Schwartz AR, et al. Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol (2003) 552(Pt 1):253–64.10.1113/jphysiol.2003.048173 PubMed DOI PMC

Xu J, Long YS, Gozal D, Epstein PN. Beta-cell death and proliferation after intermittent hypoxia: role of oxidative stress. Free Radic Biol Med (2009) 46:783–90.10.1016/j.freeradbiomed.2008.11.026 PubMed DOI

Yokoe T, Alonso LC, Romano LC, Rosa TC, O’Doherty RM, Garcia-Ocana A, et al. Intermittent hypoxia reverses the diurnal glucose rhythm and causes pancreatic beta-cell replication in mice. J Physiol (2008) 586(3):899–911.10.1113/jphysiol.2007.143586 PubMed DOI PMC

Louis M, Punjabi NM. Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol (2009) 106:1538–44.10.1152/japplphysiol.91523.2008 PubMed DOI PMC

Mesarwi O, Polak J, Jun J, Polotsky VY. Sleep disorders and the development of insulin resistance and obesity. Endocrinol Metab Clin North Am (2013) 42:617–34.10.1016/j.ecl.2013.05.001 PubMed DOI PMC

Polak J, Beamer BA, Punjabi NM. Obstructive sleep apnea and glucose metabolism. In: Allan P, editor. Sleep Apnea: Pathogenesis, Diagnosis and Treatment. New York: Informa Healthcare; (2011). p. 300–17.

Anunciato IF, Lobo RR, Coelho EB, Verri Junior WA, Eckeli AL, Évora PRB, et al. Big endothelin-1 and nitric oxide in hypertensive elderly patients with and without obstructive sleep apnea-hypopnea syndrome. Arq Bras Cardiol (2013) 101(4):344–51.10.5935/abc.20130179 PubMed DOI PMC

Gjorup PH, Sadauskiene L, Wessels J, Nyvad O, Strunge B, Pedersen EB. Abnormally increased endothelin-1 in plasma during the night in obstructive sleep apnea: relation to blood pressure and severity of disease. Am J Hypertens (2007) 20(1):44–52.10.1016/j.amjhyper.2006.05.021 PubMed DOI

Jordan W, Reinbacher A, Cohrs S, Grunewald RW, Mayer G, Ruther E, et al. Obstructive sleep apnea: plasma endothelin-1 precursor but not endothelin-1 levels are elevated and decline with nasal continuous positive airway pressure. Peptides (2005) 26:1654–60.10.1016/j.peptides.2005.02.012 PubMed DOI

Kanagy NL, Walker BR, Nelin LD. Role of endothelin in intermittent hypoxia-induced hypertension. Hypertension (2001) 37:511–5.10.1161/01.HYP.37.2.511 PubMed DOI

Phillips BG, Narkiewicz K, Pesek CA, Haynes WG, Dyken ME, Somers VK. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens (1999) 17:61–6.10.1097/00004872-199917010-00010 PubMed DOI

Saarelainen S, Seppala E, Laasonen K, Hasan J. Circulating endothelin-1 in obstructive sleep apnea. Endothelium (1997) 5(2):115–8.10.3109/10623329709079869 PubMed DOI

Zamarrón C, Riveiro A, Gude F. Circulating levels of vascular endothelial markers in obstructive sleep apnoea syndrome. Arch Med Sci (2011) 6:1023–8.10.5114/aoms.2011.26615 PubMed DOI PMC

Prabhakar NR, Kumar GK. Mechanisms of sympathetic activation and blood pressure elevation by intermittent hypoxia. Respir Physiol Neurobiol (2010) 174:156–61.10.1016/j.resp.2010.08.021 PubMed DOI PMC

Peng Y-J, Nanduri J, Zhang X, Wang N, Raghuraman G, Seagard J, et al. Endothelin-1 mediates attenuated carotid baroreceptor activity by intermittent hypoxia. J Appl Physiol (2012) 112:187–96.10.1152/japplphysiol.00529.2011 PubMed DOI PMC

Kakizawa H, Itoh M, Itoh Y, Imamura S, Ishiwata Y, Matsumoto T, et al. The relationship between glycemic control and plasma vascular endothelial growth factor and endothelin-1 concentration in diabetic patients. Metabolism (2004) 53:550–5.10.1016/j.metabol.2003.12.002 PubMed DOI

Takahashi K, Ghatei MA, Lam HC, O’Halloran DJ, Bloom SR. Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia (1990) 33:306–10.10.1007/BF00403325 PubMed DOI

Berthiaume N, Mika AK, Zinker BA. Development of insulin resistance and endothelin-1 levels in the Zucker fatty rat. Metabolism (2003) 52:845–9.10.1016/S0026-0495(03)00098-2 PubMed DOI

Takeda Y, Miyamori I, Yoneda T, Takeda R. Production of endothelin-1 from the mesenteric arteries of streptozotocin-induced diabetic rats. Life Sci (1991) 48:2553–6.10.1016/0024-3205(91)90611-E PubMed DOI

Ishibashi KI, Imamura T, Sharma PM, Huang J, Ugi S, Olefsky JM. Chronic endothelin-1 treatment leads to heterologous desensitization of insulin signaling in 3T3-L1 adipocytes. J Clin Invest (2001) 107(9):1193–202.10.1172/JCI11753 PubMed DOI PMC

Lee YC, Juan CC, Fang VS, Hsu YP, Lin SH, Kwok CF, et al. Evidence that endothelin-1 (ET-1) inhibits insulin-stimulated glucose uptake in rat adipocytes mainly through ETA receptors. Metabolism (1998) 47:1468–71.10.1016/S0026-0495(98)90071-3 PubMed DOI

Shemyakin A, Salehzadeh F, Esteves Duque-Guimaraes D, Bohm F, Rullman E, Gustafsson T, et al. Endothelin-1 reduces glucose uptake in human skeletal muscle in vivo and in vitro 1. Diabetes (2011) 60:2061–7.10.2337/db10-1281 PubMed DOI PMC

Strawbridge AB, Elmendorf JS, Mather KJ. Interactions of endothelin and insulin: expanding parameters of insulin resistance. Curr Diabetes Rev (2006) 2(3):317–27.10.2174/157339906777950642 PubMed DOI

Wilkes JJ, Hevener A, Olefsky J. Chronic endothelin-1 treatment leads to insulin resistance in vivo. Diabetes (2003) 52(8):1904–9.10.2337/diabetes.52.8.1904 PubMed DOI

Serradeil-Le GC, Jouneaux C, Sanchez-Bueno A, Raufaste D, Roche B, Preaux AM, et al. Endothelin action in rat liver. J Clin Invest (1991) 87:133–8. PubMed PMC

Chou YC, Perng JC, Juan CC, Jang SY, Kwok CF, Chen WL, et al. Endothelin-1 inhibits insulin-stimulated glucose uptake in isolated rat adipocytes. Biochem Biophys Res Commun (1994) 202:688–93.10.1006/bbrc.1994.1985 PubMed DOI

Ottosson-Seeberger A, Lundberg JM, Alvestrand A, Ahlborg G. Exogenous endothelin-1 causes peripheral insulin resistance in healthy humans. Acta Physiol Scand (1997) 161(2):211–20.10.1046/j.1365-201X.1997.00212.x PubMed DOI

Roden M, Vierhapper H, Liener K, Waldhausl W. Endothelin-1-stimulated glucose production in vitro in the isolated perfused rat liver. Metabolism (1992) 41:290–5.10.1016/0026-0495(92)90273-D PubMed DOI

Shemyakin A, Salehzadeh F, Bohm F, Al-Khalili L, Gonon A, Wagner H, et al. Regulation of glucose uptake by endothelin-1 in human skeletal muscle in vivo and in vitro. J Clin Endocrinol Metab (2010) 95:2359–66.10.1210/jc.2009-1506 PubMed DOI

Teuscher AU, Lerch M, Shaw S, Pacini G, Ferrari P, Weidmann P. Endothelin-1 infusion inhibits plasma insulin responsiveness in normal men. J Hypertens (1998) 16:1279–84.10.1097/00004872-199816090-00009 PubMed DOI

Eriksson AK, van Harmelen V, Stenson BM, Astrom G, Wahlen K, Laurencikiene J, et al. Endothelin-1 stimulates human adipocyte lipolysis through the ET A receptor. Int J Obes (2009) 33:67–74.10.1038/ijo.2008.212 PubMed DOI

Ahlborg G, Shemyakin A, Bohm F, Gonon A, Pernow J. Dual endothelin receptor blockade acutely improves insulin sensitivity in obese patients with insulin resistance and coronary artery disease. Diabetes Care (2007) 30:591–6.10.2337/dc06-1978 PubMed DOI

Balsiger B, Rickenbacher A, Boden PJ, Biecker E, Tsui J, Dashwood M, et al. Endothelin A-receptor blockade in experimental diabetes improves glucose balance and gastrointestinal function. Clin Sci (2002) 103:430S–3S.10.1042/CS103S430S PubMed DOI

Berthiaume N, Wessale JL, Opgenorth TJ, Zinker BA. Metabolic responses with endothelin antagonism in a model of insulin resistance. Metabolism (2005) 54:735–40.10.1016/j.metabol.2004.12.019 PubMed DOI

Tagaito Y, Polotsky VY, Campen MJ, Wilson JA, Balbir A, Smith PL, et al. A model of sleep-disordered breathing in the C57BL/6J mouse. J Appl Physiol (2001) 91(6):2758–66.10.1152/jappl.2001.91.6.2758 PubMed DOI

Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man 1. Diabetologia (1985) 28(7):412–9.10.1007/BF00280883 PubMed DOI

Drager LF, Li J, Reinke C, Bevans-Fonti S, Jun JC, Polotsky VY. Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity. Obesity (Silver Spring) (2011) 19:2167–74.10.1038/oby.2011.240 PubMed DOI PMC

O’Donnell CP. Metabolic consequences of intermittent hypoxia 1. Adv Exp Med Biol (2007) 618:41–9.10.1007/978-0-387-75434-5_4 PubMed DOI

Seligman BG, Biolo A, Polanczyk CA, Gross JL, Clausell N. Increased plasma levels of endothelin 1 and von Willebrand factor in patients with type 2 diabetes and dyslipidemia. Diabetes Care (2000) 23:1395–400.10.2337/diacare.23.9.1395 PubMed DOI

Allahdadi KJ, Cherng TW, Pai H, Silva AQ, Walker BR, Nelin LD, et al. Endothelin type A receptor antagonist normalizes blood pressure in rats exposed to eucapnic intermittent hypoxia 1. Am J Physiol Hear Circ Physiol (2008) 295:H434–40.10.1152/ajpheart.91477.2007 PubMed DOI PMC

Lund AK, Peterson SL, Timmins GS, Walker MK. Endothelin-1-mediated increase in reactive oxygen species and NADPH Oxidase activity in hearts of aryl hydrocarbon receptor (AhR) null mice 1. Toxicol Sci (2005) 88:265–73.10.1093/toxsci/kfi284 PubMed DOI

van Harmelen V, Eriksson A, Astrom G, Wahlen K, Naslund E, Karpe F, et al. Vascular peptide endothelin-1 links fat accumulation with alterations of visceral adipocyte lipolysis. Diabetes (2008) 57:378–86.10.2337/db07-0893 PubMed DOI

Said SA, mmar el SM, Suddek GM. Effect of bosentan (ETA/ETB receptor antagonist) on metabolic changes during stress and diabetes. Pharmacol Res (2005) 51:107–15.10.1016/j.phrs.2004.05.009 PubMed DOI

Muris DMJ, Houben AJHM, Schram MT, Stehouwer CDA. Microvascular dysfunction: an emerging pathway in the pathogenesis of obesity-related insulin resistance. Rev Endocr Metab Disord (2013) 14:29–38.10.1007/s11154-012-9231-7 PubMed DOI

Housset C, Rockey DC, Bissell DM. Endothelin receptors in rat liver: lipocytes as a contractile target for endothelin 1. Proc Natl Acad Sci U S A (1993) 90:9266–70.10.1073/pnas.90.20.9266 PubMed DOI PMC

Thomas A, Belaidi E, Moulin S, Horman S, van der Zon GC, Viollet B, et al. Chronic intermittent hypoxia impairs insulin sensitivity but improves whole-body glucose tolerance by activating skeletal muscle AMPK. Diabetes (2017) 66:2942–51.10.2337/db17-0186 PubMed DOI

Regazzetti C, Peraldi P, Gremeaux T, Najem-Lendom R, Ben-Sahra I, Cormont M, et al. Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes (2009) 58(1):95–103.10.2337/db08-0457 PubMed DOI PMC

Yin J, Gao Z, He Q, Zhou D, Guo Z, Ye J. Role of hypoxia in obesity-induced disorders of glucose and lipid metabolism in adipose tissue. Am J Physiol Endocrinol Metab (2009) 296:E333–42.10.1152/ajpendo.90760.2008 PubMed DOI PMC

Mazzuca MQ, Khalil RA. Vascular endothelin receptor type B: structure, function and dysregulation in vascular disease. Biochem Pharmacol (2012) 84:147–62.10.1016/j.bcp.2012.03.020 PubMed DOI PMC

Rapoport RM, Zuccarello M. Endothelin(A)-endothelin(B) receptor cross talk in endothelin-1-induced contraction of smooth muscle. J Cardiovasc Pharmacol (2012) 60:483–94.10.1097/FJC.0b013e31826f32c1 PubMed DOI

Kellogg DL, Liu Y, Pérgola PE. Selected contribution: gender differences in the endothelin-B receptor contribution to basal cutaneous vascular tone in humans. J Appl Physiol (2001) 91:2407–11; discussion 2389–90.10.1152/jappl.2001.91.5.2407 PubMed DOI

Borgeson DD, Grantham JA, Williamson EE, Luchner A, Redfield MM, Opgenorth TJ, et al. Chronic oral endothelin type A receptor antagonism in experimental heart failure 1. Hypertension (1998) 31(3):766–70.10.1161/01.HYP.31.3.766 PubMed DOI

Burke SE, Lubbers NL, Gagne GD, Wessale JL, Dayton BD, Wegner CD, et al. Selective antagonism of the ET(A) receptor reduces neointimal hyperplasia after balloon-induced vascular injury in pigs 1. J Cardiovasc Pharmacol (1997) 30:33–41.10.1097/00005344-199707000-00006 PubMed DOI

Potter GS, Johnson RJ, Fink GD. Role of endothelin in hypertension of experimental chronic renal failure 1. Hypertension (1997) 30:1578–84.10.1161/01.HYP.30.6.1578 PubMed DOI

Rajagopalan S, Laursen JB, Borthayre A, Kurz S, Keiser J, Haleen S, et al. Role for endothelin-1 in angiotensin II-mediated hypertension 2. Hypertension (1997) 30:29–34.10.1161/01.HYP.30.1.29 PubMed DOI

Verhaar MC, Grahn AY, Van Weerdt AW, Honing ML, Morrison PJ, Yang YP, et al. Pharmacokinetics and pharmacodynamic effects of ABT-627, an oral ETA selective endothelin antagonist, in humans 1. Br J Clin Pharmacol (2000) 49:562–73.10.1046/j.1365-2125.2000.00171.x PubMed DOI PMC

Hargrove GM, Dufresne J, Whiteside C, Muruve DA, Wong NC. Diabetes mellitus increases endothelin-1 gene transcription in rat kidney 3. Kidney Int (2000) 58(4):1534–45.10.1046/j.1523-1755.2000.00315.x PubMed DOI

Manea SA, Manea A, Heltianu C. Inhibition of JAK/STAT signaling pathway prevents high-glucose-induced increase in endothelin-1 synthesis in human endothelial cells 1. Cell Tissue Res (2010) 340(1):71–9.10.1007/s00441-010-0936-1 PubMed DOI

Verma S, Maitland A, Weisel RD, Li SH, Fedak PW, Pomroy NC, et al. Hyperglycemia exaggerates ischemia-reperfusion-induced cardiomyocyte injury: reversal with endothelin antagonism 2. J Thorac Cardiovasc Surg (2002) 123:1120–4.10.1067/mtc.2002.121973 PubMed DOI

Chester AH, Yacoub MH. The role of endothelin-1 in pulmonary arterial hypertension. Glob Cardiol Sci Pract (2014) 2014:62–78.10.5339/gcsp.2014.29 PubMed DOI PMC

Miyagawa K, Emoto N. Current state of endothelin receptor antagonism in hypertension and pulmonary hypertension. Ther Adv Cardiovasc Dis (2014) 8:202–16.10.1177/1753944714541511 PubMed DOI

Ni Z, Bemanian S, Kivlighn SD, Vaziri ND. Role of endothelin and nitric oxide imbalance in the pathogenesis of hypoxia-induced arterial hypertension. Kidney Int (1998) 54:188–92.10.1046/j.1523-1755.1998.00987.x PubMed DOI

Polak J, Shimoda LA, Drager LF, Undem C, McHugh H, Polotsky VY, et al. Intermittent hypoxia impairs glucose homeostasis in C57BL6/J mice: partial improvement with cessation of the exposure. Sleep (2013) 36:1483–90.10.5665/sleep.3040 PubMed DOI PMC

Toye AA, Lippiat JD, Proks P, Shimomura K, Bentley L, Hugill A, et al. A genetic and physiological study of impaired glucose homeostasis control in C57BL/6J mice. Diabetologia (2005) 48(4):675–86.10.1007/s00125-005-1680-z PubMed DOI

Polak J, Shimoda L, Punjabi N. Blockade of endothelin-1 receptor type B ameliorates glucose intolerance in A mouse model of sleep apnea. Am J Respir Crit Care Med (2013) 187:A2308. PubMed PMC

The Effect of Hypoxia and Metformin on Fatty Acid Uptake, Storage, and Oxidation in L6 Differentiated Myotubes

Blockade of Endothelin-1 Receptor Type B Ameliorates Glucose Intolerance and Insulin Resistance in a Mouse Model of Obstructive Sleep Apnea