Skip main navigation
Close Drawer MenuOpen Drawer Menu
Original ResearchOctober 16, 2012

Impaired Insulin Signaling in Human Adipocytes After Experimental Sleep Restriction

A Randomized, Crossover Study
    Author, Article and Disclosure Information
    https://doi.org/10.7326/0003-4819-157-8-201210160-00005
    Visual Abstract
    Full Text
    PDF
    Tools

    Chinese translation

    Background:

    Insufficient sleep increases the risk for insulin resistance, type 2 diabetes, and obesity, suggesting that sleep restriction may impair peripheral metabolic pathways. Yet, a direct link between sleep restriction and alterations in molecular metabolic pathways in any peripheral human tissue has not been shown.

    Objective:

    To determine whether sleep restriction results in reduced insulin sensitivity in subcutaneous fat, a peripheral tissue that plays a pivotal role in energy metabolism and balance.

    Design:

    Randomized, 2-period, 2-condition, crossover clinical study.

    Setting:

    University of Chicago Clinical Resource Center.

    Participants:

    Seven healthy adults (1 woman, 6 men) with a mean age of 23.7 years (SD, 3.8) and mean body mass index of 22.8 kg/m2 (SD, 1.6).

    Intervention:

    Four days of 4.5 hours in bed or 8.5 hours in bed under controlled conditions of caloric intake and physical activity.

    Measurements:

    Adipocytes collected from subcutaneous fat biopsy samples after normal and restricted sleep conditions were exposed to incremental insulin concentrations. The ability of insulin to increase levels of phosphorylated Akt (pAkt), a crucial step in the insulin-signaling pathway, was assessed. Total Akt (tAkt) served as a loading control. The insulin concentration for the half-maximal stimulation of the pAkt–tAkt ratio was used as a measure of cellular insulin sensitivity. Total body insulin sensitivity was assessed using a frequently sampled intravenous glucose tolerance test.

    Results:

    The insulin concentration for the half-maximal pAkt–tAkt response was nearly 3-fold higher (mean, 0.71 nM [SD, 0.27] vs. 0.24 nM [SD, 0.24]; P = 0.01; mean difference, 0.47 nM [SD, 0.33]; P = 0.01), and the total area under the receiver-operating characteristic curve of the pAkt–tAkt response was 30% lower (P = 0.01) during sleep restriction than during normal sleep. A reduction in total body insulin sensitivity (P = 0.02) paralleled this impaired cellular insulin sensitivity.

    Limitation:

    This was a single-center study with a small sample size.

    Conclusion:

    Sleep restriction results in an insulin-resistant state in human adipocytes. Sleep may be an important regulator of energy metabolism in peripheral tissues.

    Primary Funding Source:

    National Institutes of Health.

    References

    • 1. Hobson JA  and  Pace-Schott EF . The cognitive neuroscience of sleep: neuronal systems, consciousness and learning. Nat Rev Neurosci. 2002;3:679-93. [PMID: 12209117] CrossrefMedlineGoogle Scholar
    • 2. Stickgold R . Sleep-dependent memory consolidation. Nature. 2005;437:1272-8. [PMID: 16251952] CrossrefMedlineGoogle Scholar
    • 3. Wang G ,  Grone B ,  Colas D ,  Appelbaum L , and  Mourrain P . Synaptic plasticity in sleep: learning, homeostasis and disease. Trends Neurosci. 2011;34:452-63. [PMID: 21840068] CrossrefMedlineGoogle Scholar
    • 4. Beihl DA ,  Liese AD , and  Haffner SM . Sleep duration as a risk factor for incident type 2 diabetes in a multiethnic cohort. Ann Epidemiol. 2009;19:351-7. [PMID: 19362278] CrossrefMedlineGoogle Scholar
    • 5. Cappuccio FP ,  D'Elia L ,  Strazzullo P , and  Miller MA . Quantity and quality of sleep and incidence of type 2 diabetes: a systematic review and meta-analysis. Diabetes Care. 2010;33:414-20. [PMID: 19910503] CrossrefMedlineGoogle Scholar
    • 6. Chao CY ,  Wu JS ,  Yang YC ,  Shih CC ,  Wang RH ,  Lu FH , et al. Sleep duration is a potential risk factor for newly diagnosed type 2 diabetes mellitus. Metabolism. 2011;60:799-804. [PMID: 20846701] CrossrefMedlineGoogle Scholar
    • 7. Chaput JP ,  Després JP ,  Bouchard C ,  Astrup A , and  Tremblay A . Sleep duration as a risk factor for the development of type 2 diabetes or impaired glucose tolerance: analyses of the Quebec Family Study. Sleep Med. 2009;10:919-24. [PMID: 19332380] CrossrefMedlineGoogle Scholar
    • 8. Knutson KL . Sleep duration and cardiometabolic risk: a review of the epidemiologic evidence. Best Pract Res Clin Endocrinol Metab. 2010;24:731-43. [PMID: 21112022] CrossrefMedlineGoogle Scholar
    • 9. Patel SR  and  Hu FB . Short sleep duration and weight gain: a systematic review. Obesity (Silver Spring). 2008;16:643-53. [PMID: 18239586] CrossrefMedlineGoogle Scholar
    • 10. Rafalson L ,  Donahue RP ,  Stranges S ,  Lamonte MJ ,  Dmochowski J ,  Dorn J , et al. Short sleep duration is associated with the development of impaired fasting glucose: the Western New York Health Study. Ann Epidemiol. 2010;20:883-9. [PMID: 20620078] CrossrefMedlineGoogle Scholar
    • 11. Bosy-Westphal A ,  Hinrichs S ,  Jauch-Chara K ,  Hitze B ,  Later W ,  Wilms B , et al. Influence of partial sleep deprivation on energy balance and insulin sensitivity in healthy women. Obes Facts. 2008;1:266-73. [PMID: 20054188] CrossrefMedlineGoogle Scholar
    • 12. Buxton OM ,  Pavlova M ,  Reid EW ,  Wang W ,  Simonson DC , and  Adler GK . Sleep restriction for 1 week reduces insulin sensitivity in healthy men. Diabetes. 2010;59:2126-33. [PMID: 20585000] CrossrefMedlineGoogle Scholar
    • 13. Donga E ,  van Dijk M ,  van Dijk JG ,  Biermasz NR ,  Lammers GJ ,  van Kralingen KW , et al. A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. J Clin Endocrinol Metab. 2010;95:2963-8. [PMID: 20371664] CrossrefMedlineGoogle Scholar
    • 14. Leproult R  and  Van Cauter E . Role of sleep and sleep loss in hormonal release and metabolism. Endocr Dev. 2010;17:11-21. [PMID: 19955752] CrossrefMedlineGoogle Scholar
    • 15. Nedeltcheva AV ,  Kessler L ,  Imperial J , and  Penev PD . Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance. J Clin Endocrinol Metab. 2009;94:3242-50. [PMID: 19567526] CrossrefMedlineGoogle Scholar
    • 16. Schmid SM ,  Hallschmid M ,  Jauch-Chara K ,  Wilms B ,  Lehnert H ,  Born J , et al. Disturbed glucoregulatory response to food intake after moderate sleep restriction. Sleep. 2011;34:371-7. [PMID: 21358855] CrossrefMedlineGoogle Scholar
    • 17. Spiegel K ,  Leproult R , and  Van Cauter E . Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354:1435-9. [PMID: 10543671] CrossrefMedlineGoogle Scholar
    • 18. Ahima RS  and  Lazar MA . Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol. 2008;22:1023-31. [PMID: 18202144] CrossrefMedlineGoogle Scholar
    • 19. Morton GJ  and  Schwartz MW . Leptin and the central nervous system control of glucose metabolism. Physiol Rev. 2011;91:389-411. [PMID: 21527729] CrossrefMedlineGoogle Scholar
    • 20. Iber C ,  Ancoli-Israel S ,  Chesson A , and  Quan S . The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specification. Weschester, IL American Acad Sleep Medicine 2007. Google Scholar
    • 21. Bergman RN . Lilly lecture 1989. Toward physiological understanding of glucose tolerance. Minimal-model approach. Diabetes. 1989;38:1512-27. [PMID: 2684710] CrossrefMedlineGoogle Scholar
    • 22. Yang RZ ,  Lee MJ ,  Hu H ,  Pray J ,  Wu HB ,  Hansen BC , et al. Identification of omentin as a novel depot-specific adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol Endocrinol Metab. 2006;290:1253-61. [PMID: 16531507] CrossrefMedlineGoogle Scholar
    • 23. Tasali E ,  Leproult R ,  Ehrmann DA , and  Van Cauter E . Slow-wave sleep and the risk of type 2 diabetes in humans. Proc Natl Acad Sci U S A. 2008;105:1044-9. [PMID: 18172212] CrossrefMedlineGoogle Scholar
    • 24. Stamatakis KA  and  Punjabi NM . Effects of sleep fragmentation on glucose metabolism in normal subjects. Chest. 2010;137:95-101. [PMID: 19542260] CrossrefMedlineGoogle Scholar
    • 25. Elashoff JD . Down with multiple t-tests. Gastroenterology. 1981;80:615-20. [PMID: 7450453] CrossrefMedlineGoogle Scholar
    • 26. Hobson JA . Sleep is of the brain, by the brain and for the brain. Nature. 2005;437:1254-6. [PMID: 16251949] CrossrefMedlineGoogle Scholar
    • 27. Siegel JM . Clues to the functions of mammalian sleep. Nature. 2005;437:1264-71. [PMID: 16251951] CrossrefMedlineGoogle Scholar
    • 28. Tononi G  and  Cirelli C . Sleep function and synaptic homeostasis. Sleep Med Rev. 2006;10:49-62. [PMID: 16376591] CrossrefMedlineGoogle Scholar
    • 29. Vassalli A  and  Dijk DJ . Sleep function: current questions and new approaches. Eur J Neurosci. 2009;29:1830-41. [PMID: 19473236] CrossrefMedlineGoogle Scholar
    • 30. Björnholm M ,  Al-Khalili L ,  Dicker A ,  Näslund E ,  Rössner S ,  Zierath JR , et al. Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet. Diabetologia. 2002;45:1128-35. [PMID: 12189443] CrossrefMedlineGoogle Scholar
    • 31. Kashiwagi A ,  Verso MA ,  Andrews J ,  Vasquez B ,  Reaven G , and  Foley JE . In vitro insulin resistance of human adipocytes isolated from subjects with noninsulin-dependent diabetes mellitus. J Clin Invest. 1983;72:1246-54. [PMID: 6355180] CrossrefMedlineGoogle Scholar
    • 32. Spiegel K ,  Leproult R ,  L'hermite-Balériaux M ,  Copinschi G ,  Penev PD , and  Van Cauter E . Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab. 2004;89:5762-71. [PMID: 15531540] CrossrefMedlineGoogle Scholar
    • 33. Spiegel K ,  Tasali E ,  Penev P , and  Van Cauter E . Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141:846-50 LinkGoogle Scholar
    • 34. Kumari M ,  Badrick E ,  Ferrie J ,  Perski A ,  Marmot M , and  Chandola T . Self-reported sleep duration and sleep disturbance are independently associated with cortisol secretion in the Whitehall II study. J Clin Endocrinol Metab. 2009;94:4801-9. [PMID: 19850688] CrossrefMedlineGoogle Scholar
    • 35. Leproult R ,  Copinschi G ,  Buxton O , and  Van Cauter E . Sleep loss results in an elevation of cortisol levels the next evening. Sleep. 1997;20:865-70. [PMID: 9415946] MedlineGoogle Scholar
    • 36. Darmon P ,  Dadoun F ,  Boullu-Ciocca S ,  Grino M ,  Alessi MC , and  Dutour A . Insulin resistance induced by hydrocortisone is increased in patients with abdominal obesity. Am J Physiol Endocrinol Metab. 2006;291:995-E1002. [PMID: 16772320] CrossrefMedlineGoogle Scholar
    • 37. Fantus IG ,  Ryan J ,  Hizuka N , and  Gorden P . The effect of glucocorticoids on the insulin receptor: an in vivo and in vitro study. J Clin Endocrinol Metab. 1981;52:953-60. [PMID: 7014590] CrossrefMedlineGoogle Scholar
    • 38. Marangou AG ,  Alford FP ,  Ward G ,  Liskaser F ,  Aitken PM ,  Weber KM , et al. Hormonal effects of norepinephrine on acute glucose disposal in humans: a minimal model analysis. Metabolism. 1988;37:885-91. [PMID: 3047523] CrossrefMedlineGoogle Scholar
    • 39. Houstis N ,  Rosen ED , and  Lander ES . Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature. 2006;440:944-8. [PMID: 16612386] CrossrefMedlineGoogle Scholar
    • 40. Hücking K ,  Hamilton-Wessler M ,  Ellmerer M , and  Bergman RN . Burst-like control of lipolysis by the sympathetic nervous system in vivo. J Clin Invest. 2003;111:257-64. [PMID: 12531882] CrossrefMedlineGoogle Scholar
    • 41. Björntorp P . Adipose tissue distribution and function. Int J Obes. 1991;15: 67-81. [PMID: 1794941] MedlineGoogle Scholar
    • 42. Slieker LJ ,  Sloop KW ,  Surface PL ,  Kriauciunas A ,  LaQuier F ,  Manetta J , et al. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP. J Biol Chem. 1996;271:5301-4. [PMID: 8621378] CrossrefMedlineGoogle Scholar
    • 43. Bartness TJ ,  Vaughan CH , and  Song CK . Sympathetic and sensory innervation of brown adipose tissue. Int J Obes (Lond). 2010;34: S36-42. [PMID: 20935665] CrossrefMedlineGoogle Scholar
    Previous
    Next

    Submit a Comment

    Contributors must reveal any conflict of interest. Comments are moderated.
    Cancel