Ghrelin在阻塞性睡眠呼吸暂停综合征合并代谢综合征患者中变化及意义
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摘要
目的通过测定OSAHS患者及OSAHS合并代谢综合征患者血浆ghrelin浓度,以正常男性为对照,探讨阻塞性睡眠呼吸暂停低通气综合征(OSAHS)合并代谢综合征(MS)患者血浆ghrelin水平的变化及意义。
方法选择经我院多导睡眠图(polysomnography,PSG)检查确诊的OSAHS男性患者,据呼吸暂停/低通气指数(AHI)及是否合并代谢综合征将OSAHS组分为单纯OSAHS组(n=36例)及OSAHS合并MS组(n=14),单纯OSAHS组分为轻度(n=7例)、中度(n=10例)和重度(n=19例)3个亚组,并选取20例正常对照组及20例单纯代谢综合征对照组,测定OSAHS、MS、OSAHS合并MS患者及正常对照组血浆ghrelin水平并比较其间差异,测定持续气道正压通气(CPAP)治疗前及治疗1周后ghrelin水平并比较其变化,并比较其睡眠结构的差异。
结果1.OSAHS组的血浆ghrelin浓度(56.09±4.70)pg/ml较正常对照组(63.93±5.27)pg/ml明显下降,其差异有统计学意义(P＜0.05),而与代谢综合征组(55.91±5.50)pg/ml差别无统计学意义(P＞0.05),而OSAHS组轻中重各亚组间ghrelin浓度也无统计学差异(P＞0.05)。2.受试者最低氧饱和度(LSPO2)与ghrelin浓度显著正相关3.OSAHS合并MS组行CPAP治疗前ghrelin水平(52.74±2.68)pg/ml,治疗后(54.34±3.11)pg/ml,无明显差异(P＞0.05)。4.OSAHS组Ⅰ期睡眠(25.89±10.31)%,OSAHS合并MS组(32.19±7.47)%,较正常对照组(5.61±1.11)%明显延长,OSAHS组中慢波睡眠(Ⅲ,Ⅳ期睡眠)(11.96±5.75)%,OSAHS合并MS组(7.24±3.65)%,较正常对照组(31.36±7.34)%明显减少。
结论OSAHS及代谢综合征血浆中ghrelin水平均低于正常,ghrelin可能在OSAHS及代谢综合征的发生发展中有重要作用。
Objective:The ghrelin levels in subjects were measured to investigate the significance of the ghrelin level in Obstructive sleep apnea-hypopnea syndrome(OSAHS)associated with metabolic syndromes(MS).
Methods:Fifty OSAHS patients were enrolled after polysomnography examination and were divided into OSAHS plus MS group and OSAHS group which was further divided into mild,moderate and severe group according to the apnea hypopnea(AHI)respectively.20 healthy males were taken as control group and 20 MS patients without OSAHS as simple MS group.The ghrelin levels were measured in OSAHS group,MS group,OSAHS plus MS group and control group, before and after the continuous positive airway pressure(CPAP)treatment in OSAHS plus MS group respectively,and differences between each two groups were analysed.Furthermore,the sleep architecture of the patients in four groups has been analysed.
Results:1.The ghrelin levels in OSAHS group(n=36)[(56.03±4.75)pg/ml],MS group(n=20)[(55.91±5.50)pg/ml],OSAHS plus MS group(n=14)[(52.74±2.68)pg/ml]were significant lower than that of the control group(n=20)[(55.91±5.50)pg/ml]respectively(p＜0.05),but there was no significant difference between the OSAHS group and the MS group as in the subgroups of the OSAHS group(p＞0.05).2.The serum level of ghrelin is related to LSPO_2 positively(r=0.0903,p=0.038). 3.Baseline plasma ghrelin levels in OSAHS plus MS group(n=14) [(52.74±2.68)pg/ml]did not change significantly from the level[(54.34±3.11)pg/ml]after one week of CPAP treatment(p＞0.05).4.The incidence of hypertension in the subgroup of OSAHS group was 14.29% in mild group,25%in moderate group,73.68%in severe group and 85.71%in the OSAHS plus MS group,which was more remarkably high as OSAHS became more severe.5.The stageⅠsleep duration is (25.89±10.31)%in the OSAHS group,(32.19±7.47)%in the OSAHS plus MS group respectively,which is great drecressed in the control group(5.61±1.11)%,in the contrary,the slow wave sleep duration are (11.96±5.75)%in the OSAHS group and(7.24±3.65)%in the OSAHS associated wih MS group respectively,which is significant longer in the control group(31.36±7.34)%.
Conclusion:The plasma ghrelin levels in the OSAHS group and the MS group are both lower than that in the control group.Ghrelin may play a role in the development of OSAHS and MS.
方法选择经我院多导睡眠图(polysomnography,PSG)检查确诊的OSAHS男性患者,据呼吸暂停/低通气指数(AHI)及是否合并代谢综合征将OSAHS组分为单纯OSAHS组(n=36例)及OSAHS合并MS组(n=14),单纯OSAHS组分为轻度(n=7例)、中度(n=10例)和重度(n=19例)3个亚组,并选取20例正常对照组及20例单纯代谢综合征对照组,测定OSAHS、MS、OSAHS合并MS患者及正常对照组血浆ghrelin水平并比较其间差异,测定持续气道正压通气(CPAP)治疗前及治疗1周后ghrelin水平并比较其变化,并比较其睡眠结构的差异。
结果1.OSAHS组的血浆ghrelin浓度(56.09±4.70)pg/ml较正常对照组(63.93±5.27)pg/ml明显下降,其差异有统计学意义(P＜0.05),而与代谢综合征组(55.91±5.50)pg/ml差别无统计学意义(P＞0.05),而OSAHS组轻中重各亚组间ghrelin浓度也无统计学差异(P＞0.05)。2.受试者最低氧饱和度(LSPO2)与ghrelin浓度显著正相关3.OSAHS合并MS组行CPAP治疗前ghrelin水平(52.74±2.68)pg/ml,治疗后(54.34±3.11)pg/ml,无明显差异(P＞0.05)。4.OSAHS组Ⅰ期睡眠(25.89±10.31)%,OSAHS合并MS组(32.19±7.47)%,较正常对照组(5.61±1.11)%明显延长,OSAHS组中慢波睡眠(Ⅲ,Ⅳ期睡眠)(11.96±5.75)%,OSAHS合并MS组(7.24±3.65)%,较正常对照组(31.36±7.34)%明显减少。
结论OSAHS及代谢综合征血浆中ghrelin水平均低于正常,ghrelin可能在OSAHS及代谢综合征的发生发展中有重要作用。
Objective:The ghrelin levels in subjects were measured to investigate the significance of the ghrelin level in Obstructive sleep apnea-hypopnea syndrome(OSAHS)associated with metabolic syndromes(MS).
Methods:Fifty OSAHS patients were enrolled after polysomnography examination and were divided into OSAHS plus MS group and OSAHS group which was further divided into mild,moderate and severe group according to the apnea hypopnea(AHI)respectively.20 healthy males were taken as control group and 20 MS patients without OSAHS as simple MS group.The ghrelin levels were measured in OSAHS group,MS group,OSAHS plus MS group and control group, before and after the continuous positive airway pressure(CPAP)treatment in OSAHS plus MS group respectively,and differences between each two groups were analysed.Furthermore,the sleep architecture of the patients in four groups has been analysed.
Results:1.The ghrelin levels in OSAHS group(n=36)[(56.03±4.75)pg/ml],MS group(n=20)[(55.91±5.50)pg/ml],OSAHS plus MS group(n=14)[(52.74±2.68)pg/ml]were significant lower than that of the control group(n=20)[(55.91±5.50)pg/ml]respectively(p＜0.05),but there was no significant difference between the OSAHS group and the MS group as in the subgroups of the OSAHS group(p＞0.05).2.The serum level of ghrelin is related to LSPO_2 positively(r=0.0903,p=0.038). 3.Baseline plasma ghrelin levels in OSAHS plus MS group(n=14) [(52.74±2.68)pg/ml]did not change significantly from the level[(54.34±3.11)pg/ml]after one week of CPAP treatment(p＞0.05).4.The incidence of hypertension in the subgroup of OSAHS group was 14.29% in mild group,25%in moderate group,73.68%in severe group and 85.71%in the OSAHS plus MS group,which was more remarkably high as OSAHS became more severe.5.The stageⅠsleep duration is (25.89±10.31)%in the OSAHS group,(32.19±7.47)%in the OSAHS plus MS group respectively,which is great drecressed in the control group(5.61±1.11)%,in the contrary,the slow wave sleep duration are (11.96±5.75)%in the OSAHS group and(7.24±3.65)%in the OSAHS associated wih MS group respectively,which is significant longer in the control group(31.36±7.34)%.
Conclusion:The plasma ghrelin levels in the OSAHS group and the MS group are both lower than that in the control group.Ghrelin may play a role in the development of OSAHS and MS.
引文
1.何权瀛.阻塞性睡眠呼吸暂停低通气综合征流行病学研究的现状[J].中华结核和呼吸杂志,2003,26(5):260
2.Alexander CM,Landsman PB,Teutsch SM,et al.NCEP - defined metabolic syndrome,diabetes,and p revalence of coronary heart disease among NHANES Ⅲ participants age 50 years and older.Diabetes,2003,52:1210-1214.
3.Ohayon MM,Guilleminault C,Priest RG,et al.Is sleep2disordered breathing an independent risk factor for hypertension in the general population(13057subjects)[J].J Psychosom Res,2000,48(6):593-601.
4.Hosda H,Kojima M,Matsuo H,et al.Ghrelin and desacy ghrelin:two major forms of rat ghrelin peptide in gastrointestinal tissue.[J].Biochem Biophys Res Commun,2000,279(3):909-913
5.Weikel J.C.,Wichniak A.,Ising M.,et al.Ghrelin promotes slow-wave sleep in humans.[J].Am J Physiol Endocrinol Metab,2003,284(2):407-415
6.Harsch I.A.,Konturek RC.Leptin and ghrelin levels in patients with obstructive sleep apnea:effect of CPAP treatment.[J].Eur Respir 2003;22:251-257
7.金文胜,潘长玉.国际糖尿病联盟关于代谢综合征定义的全球共识.中华内分泌代谢杂志,2005,21(附录4b):1-2
8. Alexandras NV, Bixler EO, Chrousos GP, et al. Sleepapnea is a manifestation of the metabolic syndrome.Sleep Medicine Reviews,2005,9:211-224.
9. Mary SM, Karen SL, Ho CM, et al. Serum leptin and vascular risk factors in obstructive sleep apnea[J]. Chest ,2000 ,118(3):580-586.
10. Coughlin SR ,Mawdsley L ,Mugarza JA , et al . Obstructive sleep apnoea is indepently associated with an increased prevalence of metabolic syndrome[J]. Eur Heart J ,2004 ,25 (9):735-741.
11. Meslier N, Gagnadoux F,Giraud P, et al. Impaired glucose-insulin metabolism in males with obstructive sleep apnoea syndrome, Eur Respir[J] 2003,22:156-160.
12. Ikezaki A , Hosoda H , Ito K, et al. Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1 , but not with leptin ,in obese children and adolescents.[J]. Diabetes ,2002,51(12):3408-3411.
13. Punjabi NM, Sorkin JD, Katzel LI, et al. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med 2002,165:677-682.
14. Nakazato M, Murakami N , Date Y, et al. A role for ghrelin in the central regulation of feeding.[J]. Nature, 2001, 409:194-198.
15. cummings DE, Purnell JQ, Frayo RS, et al. Plasma ghrelin Levels after diet-induced weight loss or gastric bypass Surgery. [J]. Diabetes , 2001,50:1714-1719
16. Ciftci TU, Kokturk 0, Bukan N, et al. Leptin and Ghrelin Levels in Patients with Obstructive Sleep Apnea Syndrome. Respiration, 2005,72:395-401.
17. Loredo J S , Ancoli - Israel S , Dimsdale J E. Sleep quality and blood pressure dipping in obst ructive sleep apnea[J]. Am J Hypertens, 2001,14:887-892
18. McLaughlin T, Abbasi F, Lamendola C, et al. Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive controls. J Clin Endocrinol Metab,2004,89(4);1630-1635.
19. Poykko SM, Kellokoski E, Horkko S, et al. Low plasma ghrelin is associated with insulin resistance, hypertension ,and the prevalence of type 2diabetes. Diabetes, 2003, 52:2546-2553.
20. Marzullo P, Verti B, Savia G, et al. The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure. Clin Endocrinol Metab, 2004, 89 (2):936-939.
21. Qader SS, Lundquist I, Ekelund M, et al. Ghrelin activates neuronal constitutive nitric oxide synthase in pancreatic islet cells while inhibiting insulin release and stimulating glucagons release. Regul Pept,2005,128(1);51-56.
22. Alam I, Lewis K, Stephens JW, et al. Obesity, metabolic syndrome and sleep apnoea:all pro-inflammatory states. The International Association for the Study of Obesity. 2006, obesity reviews 8, 119-127.
23. Li WG, Gavrila D, Liu X, et al. Ghrelin inhibits proinflammatory responses and nuclear factor 2 kappa B activation in human endothelial cells. Circulation, 2004, 109:2221-2226
24. Weikel JC, Wichniak A, Ising M, et al. Ghrelin promotes slow-wave sleep in humans. Am J Physiol Endocrinol Metab,2003,284:E407-E415
1. Hosda H, Kojima M, Matsuo H, et al. Ghrelin and desacy ghrelin :two major forms of rat ghrelin peptide in gastrointestinal tissue.[J].Biochem Biophys Res Commun, 2000,279 (3):909-913
2. Harsch LA., Konturek P.C. Leptin and ghrelin levels in patients with obstructive sleep apnea: effect of CPAP treatment.[J]. Eur Respir 2003;22:251-257
3. Gualillo O, Caminos J E, Blanco M, et al. Ghrelin, A novel placental-derived hormone.[J]. Endocrinology,2001,142:788-794.
4. Hashizume T, Horiuchi M, Tate N, et al. Effects of ghrelin on growth hormone secretion from cultured adenohypophysial cellsinpigs. [J]. Domest Anim Endocrinol, 2003, 24:209-218.
5. Volante M, Allia E, Fulcheri E, et al. Ghrelin in fetal thyroid and follicular tumor and cell lines:expression and effect son tumor growth.[J]. AmJ Pathol,2003,162:645-654.
6. Leonetti F, Iacobellis G, Ribaudo MC, et al. Acute insulin infusion decreases plasma ghrelin levels in uncomplicated obesity. [J]. Regul Pept,2004,122:179-183.
7. Seiichiro F, Hidekazu S, Tatsuhiro M, et al .Enhanced ghrelin secretion in rats with cysteamine-induced duodenal ulcers.[J].Gastrointest Liver Physiol,2005,289:138.
8.Poykko M,Kellokoski E,Horkko S,et al.Low plasma ghrelin is associated with insulin resistance,hypertension,and the prevalence of type 2 diabetes.[J].Diabetes,2003,52(10):2546-2553.
9.Ip MS,Lam KS,Ho C,et al.Serum leptin and vascular risk factors in obstructive sleep apnea.[J].Chest,2000,118(3):580
10.Ikezaki A,Hosoda H,Ito K,et al.Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1,but not with leptin,in obese children and adolescents.[J].Diabetes,2002,51(12):3408-3411.
11.张希龙.殷凯生.胡玲.贾恩志.阻塞性睡眠呼吸暂停与代谢综合征相关机制的探讨.[J].实用老年医学,2004,18(5):247
12.Marzullo P,Verti B,Savia G,et al.The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure.[J].Clin Endocrinol Metab,2004,89(2):936-939.
13.Nakazato M,Murakami N,Date Y,et al.A role for ghrelin in the central regulation of feeding.[J].Nature,2001,409:194-198.
14.cummings DE,Purnell JQ,Frayo RS,et al.Plasma ghrelin Levels after diet-induced weight loss or gastric bypass Surgery.[J].Diabetes,2001,50:1714-1719
15.Shiiya T,Nakazato M,Mizutu M,et al.Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion.[J]. Clin Endocrinal Metab, 2002, 87(1); 240-244
16. Harsch LA., Konturek P.C., Koebnick C, et al. Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment.[J]. Eur Respir J 2003; 22:251-257
17. Weikel J. C, Wichniak A., Ising M.,et al. Ghrelin promotes slow-wave sleep in humans.[J]. Am J Physiol Endocrinol Metab,2003,284(2):407-415
2.Alexander CM,Landsman PB,Teutsch SM,et al.NCEP - defined metabolic syndrome,diabetes,and p revalence of coronary heart disease among NHANES Ⅲ participants age 50 years and older.Diabetes,2003,52:1210-1214.
3.Ohayon MM,Guilleminault C,Priest RG,et al.Is sleep2disordered breathing an independent risk factor for hypertension in the general population(13057subjects)[J].J Psychosom Res,2000,48(6):593-601.
4.Hosda H,Kojima M,Matsuo H,et al.Ghrelin and desacy ghrelin:two major forms of rat ghrelin peptide in gastrointestinal tissue.[J].Biochem Biophys Res Commun,2000,279(3):909-913
5.Weikel J.C.,Wichniak A.,Ising M.,et al.Ghrelin promotes slow-wave sleep in humans.[J].Am J Physiol Endocrinol Metab,2003,284(2):407-415
6.Harsch I.A.,Konturek RC.Leptin and ghrelin levels in patients with obstructive sleep apnea:effect of CPAP treatment.[J].Eur Respir 2003;22:251-257
7.金文胜,潘长玉.国际糖尿病联盟关于代谢综合征定义的全球共识.中华内分泌代谢杂志,2005,21(附录4b):1-2
8. Alexandras NV, Bixler EO, Chrousos GP, et al. Sleepapnea is a manifestation of the metabolic syndrome.Sleep Medicine Reviews,2005,9:211-224.
9. Mary SM, Karen SL, Ho CM, et al. Serum leptin and vascular risk factors in obstructive sleep apnea[J]. Chest ,2000 ,118(3):580-586.
10. Coughlin SR ,Mawdsley L ,Mugarza JA , et al . Obstructive sleep apnoea is indepently associated with an increased prevalence of metabolic syndrome[J]. Eur Heart J ,2004 ,25 (9):735-741.
11. Meslier N, Gagnadoux F,Giraud P, et al. Impaired glucose-insulin metabolism in males with obstructive sleep apnoea syndrome, Eur Respir[J] 2003,22:156-160.
12. Ikezaki A , Hosoda H , Ito K, et al. Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1 , but not with leptin ,in obese children and adolescents.[J]. Diabetes ,2002,51(12):3408-3411.
13. Punjabi NM, Sorkin JD, Katzel LI, et al. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med 2002,165:677-682.
14. Nakazato M, Murakami N , Date Y, et al. A role for ghrelin in the central regulation of feeding.[J]. Nature, 2001, 409:194-198.
15. cummings DE, Purnell JQ, Frayo RS, et al. Plasma ghrelin Levels after diet-induced weight loss or gastric bypass Surgery. [J]. Diabetes , 2001,50:1714-1719
16. Ciftci TU, Kokturk 0, Bukan N, et al. Leptin and Ghrelin Levels in Patients with Obstructive Sleep Apnea Syndrome. Respiration, 2005,72:395-401.
17. Loredo J S , Ancoli - Israel S , Dimsdale J E. Sleep quality and blood pressure dipping in obst ructive sleep apnea[J]. Am J Hypertens, 2001,14:887-892
18. McLaughlin T, Abbasi F, Lamendola C, et al. Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive controls. J Clin Endocrinol Metab,2004,89(4);1630-1635.
19. Poykko SM, Kellokoski E, Horkko S, et al. Low plasma ghrelin is associated with insulin resistance, hypertension ,and the prevalence of type 2diabetes. Diabetes, 2003, 52:2546-2553.
20. Marzullo P, Verti B, Savia G, et al. The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure. Clin Endocrinol Metab, 2004, 89 (2):936-939.
21. Qader SS, Lundquist I, Ekelund M, et al. Ghrelin activates neuronal constitutive nitric oxide synthase in pancreatic islet cells while inhibiting insulin release and stimulating glucagons release. Regul Pept,2005,128(1);51-56.
22. Alam I, Lewis K, Stephens JW, et al. Obesity, metabolic syndrome and sleep apnoea:all pro-inflammatory states. The International Association for the Study of Obesity. 2006, obesity reviews 8, 119-127.
23. Li WG, Gavrila D, Liu X, et al. Ghrelin inhibits proinflammatory responses and nuclear factor 2 kappa B activation in human endothelial cells. Circulation, 2004, 109:2221-2226
24. Weikel JC, Wichniak A, Ising M, et al. Ghrelin promotes slow-wave sleep in humans. Am J Physiol Endocrinol Metab,2003,284:E407-E415
1. Hosda H, Kojima M, Matsuo H, et al. Ghrelin and desacy ghrelin :two major forms of rat ghrelin peptide in gastrointestinal tissue.[J].Biochem Biophys Res Commun, 2000,279 (3):909-913
2. Harsch LA., Konturek P.C. Leptin and ghrelin levels in patients with obstructive sleep apnea: effect of CPAP treatment.[J]. Eur Respir 2003;22:251-257
3. Gualillo O, Caminos J E, Blanco M, et al. Ghrelin, A novel placental-derived hormone.[J]. Endocrinology,2001,142:788-794.
4. Hashizume T, Horiuchi M, Tate N, et al. Effects of ghrelin on growth hormone secretion from cultured adenohypophysial cellsinpigs. [J]. Domest Anim Endocrinol, 2003, 24:209-218.
5. Volante M, Allia E, Fulcheri E, et al. Ghrelin in fetal thyroid and follicular tumor and cell lines:expression and effect son tumor growth.[J]. AmJ Pathol,2003,162:645-654.
6. Leonetti F, Iacobellis G, Ribaudo MC, et al. Acute insulin infusion decreases plasma ghrelin levels in uncomplicated obesity. [J]. Regul Pept,2004,122:179-183.
7. Seiichiro F, Hidekazu S, Tatsuhiro M, et al .Enhanced ghrelin secretion in rats with cysteamine-induced duodenal ulcers.[J].Gastrointest Liver Physiol,2005,289:138.
8.Poykko M,Kellokoski E,Horkko S,et al.Low plasma ghrelin is associated with insulin resistance,hypertension,and the prevalence of type 2 diabetes.[J].Diabetes,2003,52(10):2546-2553.
9.Ip MS,Lam KS,Ho C,et al.Serum leptin and vascular risk factors in obstructive sleep apnea.[J].Chest,2000,118(3):580
10.Ikezaki A,Hosoda H,Ito K,et al.Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1,but not with leptin,in obese children and adolescents.[J].Diabetes,2002,51(12):3408-3411.
11.张希龙.殷凯生.胡玲.贾恩志.阻塞性睡眠呼吸暂停与代谢综合征相关机制的探讨.[J].实用老年医学,2004,18(5):247
12.Marzullo P,Verti B,Savia G,et al.The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure.[J].Clin Endocrinol Metab,2004,89(2):936-939.
13.Nakazato M,Murakami N,Date Y,et al.A role for ghrelin in the central regulation of feeding.[J].Nature,2001,409:194-198.
14.cummings DE,Purnell JQ,Frayo RS,et al.Plasma ghrelin Levels after diet-induced weight loss or gastric bypass Surgery.[J].Diabetes,2001,50:1714-1719
15.Shiiya T,Nakazato M,Mizutu M,et al.Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion.[J]. Clin Endocrinal Metab, 2002, 87(1); 240-244
16. Harsch LA., Konturek P.C., Koebnick C, et al. Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment.[J]. Eur Respir J 2003; 22:251-257
17. Weikel J. C, Wichniak A., Ising M.,et al. Ghrelin promotes slow-wave sleep in humans.[J]. Am J Physiol Endocrinol Metab,2003,284(2):407-415
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