Visceral Obesity is Associated with the Metabolic Syndrome and Elevated Plasma Retinol Binding Protein-4 Level in Obstructive Sleep Apnea Syndrome

Abstract

Obstructive sleep apnea syndrome (OSAS) is related to the increased prevalence of cardiovascular disease and metabolic syndrome (MS). A novel adipokine, retinol binding protein-4 (RBP4), was reported to be associated with insulin resistance and the prevalence of type 2 diabetes. To examine whether plasma RBP4 is associated with insulin resistance and MS development in OSAS, we measured plasma RBP4 levels in 181 Japanese men (24 healthy controls and 40 mild, 64 moderate, and 53 severe OSAS) of whom 26 had mild glucose intolerance with HbA1c ≦6.0%. After a full polysomnography, blood was collected between 06:00 and 07:00 AM. Plasma RBP4 levels in moderate/severe OSAS patients were higher than in control subjects. Plasma RBP4 was not correlated with apnea variables, HOMA-IR, or blood pressure. However, it was positively correlated with visceral fat areas and plasma triglyceride levels. The prevalence of MS was higher in severe OSAS patients than in mild/moderate OSAS and control subjects. Plasma RBP4 was higher in OSAS patients with MS than in those without MS. This study indicates that plasma RBP4 is associated with dyslipidemia, but not with insulin resistance, glucose intolerance, or hypertension in patients with OSAS. Visceral obesity may play key roles in increasing the plasma RBP4 level and MS development in OSAS.

Key words

sleep apnea - retinol binding protein-4 - metabolic syndrome

References

• 1 Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR, Smith PL. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men.  Am J Respir Crit Care Med. 2002;  165 677-682
• 2 Ip MSP, Lam B, Ng MMT, Lam WK, Tsang KWT, Lam KSL. Obstructive sleep apnea is independently associated with insulin resistance.  Am J Respir Crit Care Med. 2002;  165 670-676
• 3 Makino S, Handa H, Suzukawa K, Fujiwara M, Nakamura M, Muraoka S, Takasago I, Tanaka Y, Hashimoto K, Sugimoto T. Obstructive sleep apnoea syndrome, plasma adiponectin levels, and insulin resistance.  Clin Endocrinol (Oxf). 2006;  64 12-19
• 4 Nieto FJ, Young TB, Ling BK, Shahar E, Samet JM, Redline S, D’Agostino RB, Newman AB, Lebowitz MD, Pickering TG. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study.  JAMA. 2000;  283 1829-1836
• 5 Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep disordered breathing and hypertension.  New Engl J Med. 2000;  342 1378-1384
• 6 Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome.  Sleep Med Rev. 2005;  9 211-224
• 7 Vgontzas AN, Papanicolou DA, Bixler EO, Hopper K, Lotsikas A, Lin H, Kales A, Chrousos GP. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia.  J Clin Endocrinol Metab. 2000;  85 1151-1158
• 8 Shamsuzzaman AS, Winnicki M, Lanfranchi P, Wolk R, Kara T, Accurso V, Somers VK. Elevated C-reactive protein in patients with obstructive sleep apnea.  Circulation. 2002;  105 2462-2464
• 9 Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, Hirano T, Adachi M. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure.  Circulation. 2003;  107 1129-1134
• 10 Minoguchi K, Tazaki T, Yokoe T, Minoguchi H, Watanabe Y, Yamamoto M, Adachi M. Elevated production of tumor necrosis factor-alpha by monocytes in patients with obstructive sleep apnea syndrome.  Chest. 2004;  126 1473-1479
• 11 Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, Kotani K, Quadro L, Kahn BB. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.  Nature. 2005;  436 356-362
• 12 Tamori Y, Sakaue H, Kasuga M. RBP4, an unexpected adipokine.  Nat Med. 2006;  12 30-31
• 13 Cho YM, Youn BS, Lee H, Lee N, Min SS, Kwak SH, Lee HK, Park KS. Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes.  Diabetes Care. 2006;  29 2457-2461
• 14 Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects.  N Engl J Med. 2006;  354 2552-2563
• 15 Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Schleicher E, Fritsche A, Haring HU. High circulating retinol-binding protein 4 is associated with elevated liver fat but not with total, subcutaneous, visceral, or intramyocellular fat in humans.  Diabetes Care. 2007;  30 1173-1178
• 16 Gavi S, Stuart LM, Kelly P, Melendez MM, Mynarcik DC, Gelato MC, MacNurlan MA. Retinol-binding protein 4 is associated with insulin resistance and body fat distribution in nonobese subjects without type 2 diabetes.  J Clin Endocrinol Metab. 2007;  92 1886-1890
• 17 Lee DC, Lee JW, Im JA. Association of serum retinol binding protein 4 and insulin resistance in apparently healthy adolescents.  Metabolism. 2007;  56 327-331
• 18 Qi Q, Yu Z, Ye X, Zhao F, Huang P, Hu FB, Franco OH, Wang J, Li H, Liu Y, Lin X. Elevated retinol-binding protein 4 levels are associated with metabolic syndrome in Chinese people.  J Clin Endocrinol Metab. 2007;  92 4827-4834
• 19 Takashima N, Tomoike H, Iwai N. Retinol-binding protein 4 and insulin resistance.  N Engl J Med. 2006;  355 1392
• 20 Silha JV, Nyomba BL, Leslie WD, Murphy LJ. Ethnicity, insulin resistance, and inflammatory adipokines in women at high and low risk for vascular disease.  Diabetes Care. 2007;  30 286-291
• 21 Shin MJ, Kang SM, Jang Y, Lee JH, Oh J, Chung JH, Chung N. Serum retinol binding protein 4 levels are associated with serum adiponectin levels in non-diabetic, non-obese subjects with hypercholesterolemia.  Clin Chim Acta. 2007;  378 227-229
• 22 Eynatten M von, Lepper PM, D L, Lang K, Baumann M, Nawroth PP, Bierhaus A, Dugi KA, Heemann U, Allolio B, Humpert PM. Retinol-binding protein 4 is associated with components of the metabolic syndrome, but not with insulin resistance, in men with type 2 diabetes or coronary artery disease.  Diabetologia. 2007;  50 1930-1937
• 23 Funahashi T, Matsuzawa Y. Metabolic syndrome: clinical concept and molecular basis.  Ann Med. 2007;  39 482-494
• 24 Matsuzawa Y. Metabolic syndrome – definition and diagnostic criteria in Japan.  J Atheroscler Thromb. 2005;  12 301
• 25 Sone H, Tanaka S, Ishibashi S, Yamasaki Y, Oikawa S, Ito H, Saito Y, Ohashi Y, Akanuma Y, Yamada N. Group JDCSJ . The new worldwide definition of metabolic syndrome is not a better diagnostic predictor of cardiovascular disease in Japanese diabetic patients than the existing definitions: additional analysis from the Japan Diabetes Complications Study.  Diabetes Care. 2006;  29 145-147
• 26 Jia W, Wu H, Bao Y, Wang C, Lu J, Zhu J, Xiang K. Association of serum retinol binding protein 4 and visceral adiposity in chinese subjects with and without type 2 diabetes.  J Clin Endocrinol Metab. 2007;  92 3224-3229
• 27 Yao-Borengasser A, Varma V, Bodles AM, Rasouli N, Phanavanh B, Lee MJ, Starks T, Kern LM, Spencer Jr H, AA R, MacGehee REJ, SK F, Kern PA. Retinol binding protein 4 expression in humans: relationship to insulin resistance, inflammation, and response to pioglitazone.  J Clin Endocrinol Metab. 2007;  92 2590-2597
• 28 Fujioka S, Matsuzawa Y, Tokunaga K, Tarui S. Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity.  Metabolism. 1987;  36 54-59
• 29 Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β cell function from fasting plasma glucose and insulin concentrations in man.  Diabetologia. 1985;  28 412-419
• 30 Emoto M, Nishizawa Y, Maekawa K, Hiura Y, Kanda H, Kawagishi T, Shoji T, Okuno Y, Morii H. Homeostasis model assessment as a clinical index of insulin resistance in type 2 diabetic patients treated with sulfonylureas.  Diabetes Care. 1999;  22 818-822
• 31 Janke J, Engeli S, Boschmann M, Adams F, Bohnke J, Luft FC, Sharma AM, Jordan J. Retinol-binding protein 4 in human obesity.  Diabetes. 2006;  55 2805-2810
• 32 Erikstrup C, Mortensen OH, Pedersen BK. Retinol-binding protein 4 and insulin resistance.  N Engl J Med. 2006;  355 1393-1394
• 33 Gavi S, Qurashi S, Stuart LM, Lau R, Melendez MM, Mynarcik DC, MacNurlan MA, Gelato MC. Influence of age on the association of retinol-binding protein 4 with metabolic syndrome.  Obesity (Silver Spring). 2008;  16 893-895
• 34 Graham TE, Wason CJ, Bluher M, Kahn BB. Shortcomings in methodology complicate measurements of serum retinol binding protein (RBP4) in insulin-resistant human subjects.  Diabetologia. 2007;  50 814-823
• 35 Ryan S, Taylor CT, MacNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome.  Circulation. 2005;  112 2660-2667
• 36 Lee JW, Lee HR, Shim JY, Im JA, Lee DC. Abdominal visceral fat reduction is associated with favorable changes of serum retinol binding protein-4 in nondiabetic subjects.  Endocr J. 2008;  , [in press]
• 37 Tsutsumi C, Okuno M, Tannous L, Piantedosi R, Allan M, Goodman DS, Blaner WS. Retinoids and retinoid-binding protein expression in rat adipocytes.  J Biol Chem. 1992;  267 1805-1810
• 38 Takebayashi K, Suetsugu M, Wakabayashi S, Aso Y, Inukai T. Retinol binding protein-4 levels and clinical features of type 2 diabetes patients.  J Clin Endocrinol Metab. 2007;  92 2712-2719
• 39 Koistinen HA, Remitz A, Gylling H, Miettinen TA, Koivisto VA, Ebeling P. Dyslipidemia and a reversible decrease in insulin sensitivity induced by therapy with 13-cis-retinoic acid.  Diabetes Metab Res Rev. 2001;  17 391-395
• 40 Rodondi N, Darioli R, Ramelet AA, Hohl D, Lenain V, Perdrix J, Wietlisbach V, Riesen WF, Walther T, Medinger L, Nicod P, Desvergne B, Mooser V. High risk for hyperlipidemia and the metabolic syndrome after an episode of hypertriglyceridemia during 13-cis retinoic acid therapy for acne: a pharmacogenetic study.  Ann Intern Med. 2002;  136 582-589
• 41 Choi SH, Kwak SH, Youn BS, Lim S, Park YJ, Lee H, Lee N, Cho YM, Lee HK, Kim YB, Park KS, Jang HC. High plasma retinol binding protein-4 and low plasma adiponectin concentrations are associated with severity of glucose intolerance in women with previous gestational diabetes mellitus.  J Clin Endocrinol Metab. 2008;  93 3142-3148
• 42 Iwaki M, Matsuda M, Maeda N, Funahashi T, Matsuzawa Y, Makishima M, Shimomura I. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors.  Diabetes. 2003;  52 1655-1663
• 43 Maeda N, Shimomura I, Kishida K, Nishizawa H, Matsuda M, Nagaretani H, Furuyama N, Kondo H, Takahashi M, Arita Y, Komuro R, Ouchi N, Kihara S, Tochino Y, Okutomi K, Horie M, Takeda S, Aoyama T, Funahashi T, Matsuzawa Y. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30.  Nat Med. 2002;  8 731-737
• 44 Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome.  Arterioscler Thromb Vasc Biol. 2004;  24 29-33
• 45 Ng TW, Watts GF, Barrett PH, Rye KA, Chan DC. Effect of weight loss on LDL and HDL kinetics in the metabolic syndrome: associations with changes in plasma retinol-binding protein-4 and adiponectin levels.  Diabetes Care. 2007;  30 2945-2950

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