Skip to main content
SpringerLink
Log in

The relations of circulating agouti-related peptide and leptin with altered sleep architecture in patients with active Cushing’s disease: a pilot study

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Aim

To evaluate sleep architecture of patients with Cushing’s disease (CD) and to explore whether agouti-related peptide (AgRP) and/or leptin play a permissive role in sleep alterations in patients with active CD.

Methods

We performed polysomnography on 26 patients with active CD and age 26 age- and sex-matched control subjects. Blood samples were obtained from all participants for the analyzes of AgRP and leptin. The laboratory and sleep-related parameters were compared.

Results

The groups were similar in age, gender, and body mass index. The CD group had reduced sleep efficiency (71.6 ± 12.1% vs. 78.8 ± 12.6%, p = 0.042) and increased wake after sleep onset (WASO%) (24.7 ± 13.1% vs. 17.4 ± 11.6%, p = 0.040) as compared to control group. Seventeen patients with CD (65.4%) and 18 control subjects (69.2%) had obstructive sleep apnea. Serum AgRP (13.2 ± 7.4 pg/ml vs. 9 ± 3.1, p = 0.029), leptin (59.5 mcg/l, [IQR] 32.6–94.6 vs. 25.3 mcg/l, [IQR] 12.9–57.5, p = 0.007) were higher in CD group. AgRP and leptin correlated negatively with total sleep time, sleep efficiency, stage N2 sleep (%), and positively with WASO%. In multiple regression analyses, serum cortisol (ß =  − 0.359, p = 0.042) and AgRP (ß =  − 0.481, p = 0.01) were significant predictor of sleep efficiency. AgRP was also significant predictor of WASO% (ß = 0.452 and p < 0.05).

Conclusions

Active CD carries an increased risk of impaired sleep efficiency and continuity which may worsen health-related quality of life. Elevated circulating AgRP and, to a lesser extent, leptin may be associated with decreased sleep efficiency and continuity in patients with CD. Patients with CD who have subjective sleep symptoms should be screened with polysomnography.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this article [and/or] its tables. The data repository can be provided upon request. Further inquiries can be directed to the corresponding author.

References

  1. Starkman MN, Schteingart DE, Schork MA (1981) Depressed mood and other psychiatric manifestations of Cushing’s syndrome: relationship to hormone levels. Psychosom Med 43:3–18

    Article  PubMed  CAS  Google Scholar 

  2. Shipley JE, Schteingart DE, Tandon R et al (1992) Sleep architecture and sleep apnea in patients with Cushing’s disease. Sleep 15:514–518

    Article  PubMed  CAS  Google Scholar 

  3. Starkman MN, Schteingart DE (1981) Neuropsychiatric manifestations of patients with Cushing’s syndrome: relationship to cortisol and adrenocorticotropic hormone levels. Arch Intern Med 141:215–219

    Article  PubMed  CAS  Google Scholar 

  4. Ismailogullari S, Karaca Z, Firat ST et al (2021) Cushing syndrome is associated with increased stage N2 sleep and decreased SWS partially reversible after treatment. Horm Metab Res 53:608–615

    Article  PubMed  CAS  Google Scholar 

  5. Friedman TC, García-Borreguero D, Hardwick D et al (1994) Decreased delta-sleep and plasma delta-sleep-inducing peptide in patients with Cushing syndrome. Neuroendocrinology 60:626–634

    Article  PubMed  CAS  Google Scholar 

  6. Mazziotti G, Giustina A (2013) Glucocorticoids and the regulation of growth hormone secretion. Nat Rev Endocrinol 9:265–276

    Article  PubMed  CAS  Google Scholar 

  7. Buckley TM, Schatzberg AF (2005) On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. J Clin Endocrinol Metab 90:3106–3114

    Article  PubMed  CAS  Google Scholar 

  8. Steiger A (2002) Sleep and the hypothalamo–pituitary–adrenocortical system. Sleep Med Rev 6:125–138

    Article  PubMed  Google Scholar 

  9. Bottini P, Tantucci C (2003) Sleep apnea syndrome in endocrine diseases. Respiration 70:320–327

    Article  PubMed  Google Scholar 

  10. Danguir J, Nicolaïdis S, Gerard H (1979) Relations between feeding and sleep patterns in the rat. J Comp Physiol Psychol 93:820

    Article  Google Scholar 

  11. Garcı́a-Garcı́a F, Drucker-Colı́n R (1999) Endogenous and exogenous factors on sleep–wake cycle regulation. Progr Neurobiol 58:297–314

    Article  Google Scholar 

  12. Richter C, Woods IG, Schier AF (2014) Neuropeptidergic control of sleep and wakefulness. Annu Rev Neurosci 37:503–531

    Article  PubMed  CAS  Google Scholar 

  13. Ollmann MM, Wilson BD, Yang Y-K et al (1997) Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278:135–138

    Article  PubMed  CAS  Google Scholar 

  14. Park H-K, Ahima RS (2015) Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism 64:24–34

    Article  PubMed  CAS  Google Scholar 

  15. Cedernaes J, Huang W, Ramsey KM et al (2019) Transcriptional basis for rhythmic control of hunger and metabolism within the AgRP neuron. Cell Metab 29:1078-1091.e1075

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Goldstein N, Levine BJ, Loy KA et al (2018) Hypothalamic neurons that regulate feeding can influence sleep/wake states based on homeostatic need. Curr Biol 28(3736–3747):e3733

    Google Scholar 

  17. Koo M, Lai N-S, Chiang J-K (2013) Short duration of sleep is associated with hyperleptinemia in Taiwanese adults. J Clin Sleep Med 9:1049–1055

    Article  PubMed  PubMed Central  Google Scholar 

  18. Olson CA, Hamilton NA, Somers VK (2016) Percentage of REM sleep is associated with overnight change in leptin. J Sleep Res 25:419–425

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sinton CM, Fitch TE, Gershenfeld HK (1999) The effects of leptin on REM sleep and slow wave deltain rats are reversed by food deprivation. J Sleep Res 8:197–203

    Article  PubMed  CAS  Google Scholar 

  20. Laposky AD, Shelton J, Bass J et al (2006) Altered sleep regulation in leptin-deficient mice. Am J Physiol-Regul, Integr Comp Physiol 290:R894–R903

    Article  PubMed  CAS  Google Scholar 

  21. Laposky AD, Bradley MA, Williams DL et al (2008) Sleep-wake regulation is altered in leptin-resistant (db/db) genetically obese and diabetic mice. Am J Physiol-Regul, Integr Comp Physiol 295:R2059–R2066

    Article  PubMed  CAS  Google Scholar 

  22. Page-Wilson G, Freda PU, Jacobs TP et al (2014) Clinical utility of plasma POMC and AgRP measurements in the differential diagnosis of ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab 99:E1838-1845

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Page-Wilson G, Peters JB, Panigrahi SK et al (2019) Plasma agouti-related protein and cortisol levels in cushing disease: evidence for the regulation of agouti-related protein by glucocorticoids in humans. J Clin Endocrinol Metab 104:961–969

    Article  PubMed  Google Scholar 

  24. Veldman RG, Frolich M, Pincus SM et al (2001) Hyperleptinemia in women with Cushing’s disease is driven by high-amplitude pulsatile, but orderly and eurhythmic, leptin secretion. Eur J Endocrinol 144:21–27

    Article  PubMed  CAS  Google Scholar 

  25. Schafroth U, Godang K, Ueland T et al (2000) Leptin levels in relation to body composition and insulin concentration in patients with endogenous Cushing’s syndrome compared to controls matched for body mass index. J Endocrinol Invest 23:349–355

    Article  PubMed  CAS  Google Scholar 

  26. Nieman LK, Biller BMK, Findling JW et al (2008) The diagnosis of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 93:1526–1540

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Association AD (2020) 6. Glycemic targets: standards of medical care in diabetes-2020. Diabetes Care 43:S66–S76

    Article  Google Scholar 

  28. James PA, Oparil S, Carter BL et al (2014) 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth joint national committee (JNC 8). JAMA 311:507–520

    Article  PubMed  CAS  Google Scholar 

  29. Berry RB, Brooks R, Gamaldo CE et al (2012) The AASM manual for the scoring of sleep and associated events. Rules Terminol Tech Specific Darien Illinois Am Acad Sleep Med 176:2012

    Google Scholar 

  30. Medicine AAoS International Classification of Sleep Disorders 2014 3rd ed Darien. IL American Academy of Sleep Medicine. pp 246–253

  31. Johns MW (2000) Sensitivity and specificity of the multiple sleep latency test (MSLT), the maintenance of wakefulness test and the Epworth sleepiness scale: failure of the MSLT as a gold standard. J Sleep Res 9:5–11

    Article  PubMed  CAS  Google Scholar 

  32. Buysse DJ, Reynolds CF III, Monk TH et al (1991) Quantification of subjective sleep quality in healthy elderly men and women using the Pittsburgh Sleep Quality Index (PSQI). Sleep 14:331–338

    PubMed  CAS  Google Scholar 

  33. Bertagna X, Guignat L (2013) Approach to the Cushing’s disease patient with persistent/recurrent hypercortisolism after pituitary surgery. J Clin Endocrinol Metab 98:1307–1318

    Article  PubMed  CAS  Google Scholar 

  34. D’Angelo V, Beccuti G, Berardelli R et al (2015) Cushing’s syndrome is associated with sleep alterations detected by wrist actigraphy. Pituitary 18:893–897

    Article  PubMed  Google Scholar 

  35. Romijn JA (2016) Pituitary diseases and sleep disorders. Curr Opin Endocrinol Diabetes Obes 23:345–351

    Article  PubMed  Google Scholar 

  36. Krieger D (1975) Sleep EEG stages and growth hormone levels in endogenous and exogenous hyper-cortisolemia or ACTH elevation. Prog Brain Res 42:121

    Article  PubMed  CAS  Google Scholar 

  37. Krieger DT, Glick SM (1974) Sleep EEG stages and plasma growth hormone concentration in states of endogenous and exogenous hypercortisolemia or ACTH elevation. J Clin Endocrinol Metab 39:986–1000

    Article  PubMed  CAS  Google Scholar 

  38. Zakrzewska KE, Cusin I, Stricker-Krongrad A et al (1999) Induction of obesity and hyperleptinemia by central glucocorticoid infusion in the rat. Diabetes 48:365–370

    Article  PubMed  CAS  Google Scholar 

  39. Panigrahi SK, Toedesbusch CD, McLeland JS et al (2020) Diurnal patterns for cortisol, cortisone and agouti-related protein in human cerebrospinal fluid and blood. J Clin Endocrinol Metab 105:e1584-1592

    Article  PubMed  Google Scholar 

  40. Padilla SL, Qiu J, Soden ME et al (2016) Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state. Nat Neurosci 19:734–741

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Shibata M, Banno R, Sugiyama M et al (2016) AgRP neuron-specific deletion of glucocorticoid receptor leads to increased energy expenditure and decreased body weight in female mice on a high-fat diet. Endocrinology 157:1457–1466

    Article  PubMed  CAS  Google Scholar 

  42. Hagimoto S, Arima H, Adachi K et al (2013) Expression of neuropeptide Y and agouti-related protein mRNA stimulated by glucocorticoids is attenuated via NF-κB p65 under ER stress in mouse hypothalamic cultures. Neurosci Lett 553:165–169

    Article  PubMed  CAS  Google Scholar 

  43. Shimizu H, Arima H, Watanabe M et al (2008) Glucocorticoids increase neuropeptide Y and agouti-related peptide gene expression via adenosine monophosphate-activated protein kinase signaling in the arcuate nucleus of rats. Endocrinology 149:4544–4553

    Article  PubMed  CAS  Google Scholar 

  44. Szentirmai É (2012) Central but not systemic administration of ghrelin induces wakefulness in mice. PLoS ONE 7:e41172

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Weber F, Dan Y (2016) Circuit-based interrogation of sleep control. Nature 538:51–59

    Article  PubMed  CAS  Google Scholar 

  46. Ramírez-Plascencia OD, Saderi N, Cárdenas-Romero S et al (2022) Leptin and adiponectin regulate the activity of nuclei involved in sleep-wake cycle in male rats. Front Neurosci. https://doi.org/10.3389/fnins.2022.907508

    Article  PubMed  PubMed Central  Google Scholar 

  47. Megirian D, Dmochowski J, Farkas GA (1998) Mechanism controlling sleep organization of the obese Zucker rats. J Appl Physiol 84:253–256

    Article  PubMed  CAS  Google Scholar 

  48. Hirota T, Morioka T, Yoda K et al (2018) Positive association of plasma leptin with sleep quality in obese type 2 diabetes patients. J Diabetes Investig 9:1100–1105

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Friess E, Wiedemann K, Steiger A et al (1995) The hypothalamic-pituitary-adrenocortical system and sleep in man. Adv Neuroimmunol 5:111–125

    Article  PubMed  CAS  Google Scholar 

  50. Leal-Cerro A, Soto A, Martínez MA et al (2001) Influence of cortisol status on leptin secretion. Pituitary 4:111–116

    Article  PubMed  CAS  Google Scholar 

  51. Pan W, Kastin AJ (2014) Leptin: a biomarker for sleep disorders? Sleep Med Rev 18:283–290

    Article  PubMed  Google Scholar 

  52. Knutson K, Galli G, Zhao X et al (2011) NIDDK sleep extension study. No association between leptin levels and sleep duration or quality in obese adults. Obesity 19:2433–2435

    Article  PubMed  CAS  Google Scholar 

  53. Capers PL, Fobian AD, Kaiser KA et al (2015) A systematic review and meta-analysis of randomized controlled trials of the impact of sleep duration on adiposity and components of energy balance. Obes Rev 16:771–782

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Pattipati M, Gudavalli G (2022) Association between Cushing’s syndrome and sleep apnea: results from the national inpatient sample. Cureus 14:e22044

    PubMed  PubMed Central  Google Scholar 

  55. Gokosmanoğlu F, Güzel A, Kan EK et al (2017) Increased prevalence of obstructive sleep apnea in patients with Cushing’s syndrome compared with weight- and age-matched controls. Eur J Endocrinol 176:267–272

    Article  PubMed  Google Scholar 

  56. Buysse DJ, Reynolds CF 3rd, Monk TH et al (1989) The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Res 28:193–213

    Article  PubMed  CAS  Google Scholar 

  57. Sagan KP, Andrysiak-Mamos E, Tyburski E et al (2021) Quality of life and sleep in patients with pituitary adenoma in relation to tumor type and compression of the optic chiasm. J Clin Med 10:1879

    Article  PubMed  PubMed Central  Google Scholar 

  58. Chen DM, Taporoski TP, Alexandria SJ et al (2023) Altered sleep architecture in diabetes and prediabetes: findings from the Baependi Heart Study. medRxiv. 252:125

    Google Scholar 

  59. Yoda K, Inaba M, Hamamoto K et al (2015) Association between poor glycemic control, impaired sleep quality, and increased arterial thickening in type 2 diabetic patients. PLoS ONE 10:e0122521

    Article  PubMed  PubMed Central  Google Scholar 

  60. Pallayova M, Donic V, Gresova S et al (2010) Do differences in sleep architecture exist between persons with type 2 diabetes and nondiabetic controls? J Diabetes Sci Technol 4:344–352

    Article  PubMed  PubMed Central  Google Scholar 

  61. Kajbaf F, Fendri S, Basille-Fantinato A et al (2014) The relationship between metformin therapy and sleep quantity and quality in patients with Type 2 diabetes referred for potential sleep disorders. Diabet Med 31:577–580

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

The present study was funded by Scientific Research Projects Coordination Unit of Istanbul University-Cerrahpasa (Grant No: 2021–35750).

Author information

Authors and Affiliations

  1. Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Kocamustafapasa Street No:53, Fatih, 34098, Istanbul, Turkey

    C. Sulu, A. N. Demir, H. M. Ozkaya & P. Kadioglu

  2. Sleep and Disorders Unit, Department of Neurology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey

    G. B. Senel & D. Karadeniz

  3. Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey

    O. Koca

  4. Department of Neuroscience, Institute of Neurological Sciences, Istanbul University-Cerrahpasa, Istanbul, Turkey

    M. Alaylioglu, D. G. Ak & E. Dursun

  5. Department of Endocrinology, Bagcilar Training Hospital, Istanbul, Turkey

    E. Durcan

  6. Department of Biochemistry, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey

    D. Konukoglu

  7. Pituitary Center, Istanbul University-Cerrahpasa, Istanbul, Turkey

    H. M. Ozkaya & P. Kadioglu

Authors
  1. C. Sulu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. B. Senel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. O. Koca
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Alaylioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. N. Demir
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Durcan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D. G. Ak
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. E. Dursun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D. Konukoglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. H. M. Ozkaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D. Karadeniz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. P. Kadioglu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors made substantial contributions to the conception and design, and/or acquisition of data, and/or analysis and interpretation of data; participated in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be submitted.

Corresponding author

Correspondence to P. Kadioglu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The present study was approved by the Medical Research Ethics Committee of Cerrahpasa Medical School (01.14.2021-7774). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration.

Consent to participate

Informed consent was obtained from all participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sulu, C., Senel, G.B., Koca, O. et al. The relations of circulating agouti-related peptide and leptin with altered sleep architecture in patients with active Cushing’s disease: a pilot study. J Endocrinol Invest 47, 167–178 (2024). https://doi.org/10.1007/s40618-023-02133-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-023-02133-0

Keywords

Search

Navigation