, Volume 58, Issue 4, pp 651–653 | Cite as

Are we waking up to the effects of NEFA?

  • Jonathan C. JunEmail author
  • Vsevolod Y. Polotsky


NEFA are mobilised from adipose tissues during fasting or stress. Under conditions of acute or chronic NEFA excess, skeletal muscle and hepatic insulin resistance may ensue. Hence, a wealth of literature has focused on the crosstalk between NEFA and glucose in the pathogenesis of insulin resistance. Sleep restriction has also been shown to acutely induce insulin resistance, and self-reported short sleep duration is associated with diabetes. In this issue of Diabetologia (DOI:  10.1007/s00125-015-3500-4), Broussard and colleagues examine the impact of acute sleep restriction on detailed 24 h metabolic profiles, including plasma NEFA. Here, we address the potential clinical relevance of these findings and pose questions for further research.


Diabetes Fatty acids NEFA Sleep restriction 

Sleep loss, often resulting from voluntary sleep restriction, has become a norm of modern society. Beyond obvious cognitive impairments caused by lack of sleep, other detrimental health consequences are becoming apparent. As average sleep duration has declined, the incidence of diabetes and obesity has risen, and this phenomenon may be more than coincidence [1]: short sleep duration has been identified as a risk factor for incident type 2 diabetes in prospective studies [2, 3]. There is also direct evidence that sleep is critical for glucose homeostasis. A landmark study performed at the University of Chicago in 1999 restricted the sleep of healthy men to 4 h per night for six nights, followed by six nights of recovery sleep. Sleep restriction significantly impaired glucose tolerance, reduced glucose effectiveness and reduced the acute insulin response to glucose. HOMA of the glucose and insulin profiles also suggested peripheral insulin resistance [4]. In addition, sleep restriction may promote obesity [5, 6] by stimulating appetite [7, 8] while providing increased eating opportunities [9]. It may therefore play an unrecognised role in the epidemic of obesity and type 2 diabetes. However, the mechanisms underlying this relationship are not known.

In 1963, Randle, Garland, Hales and Newsholme proposed the ‘glucose–fatty acid cycle’, observing that NEFA availability and utilisation in tissues inhibited glucose oxidation, and vice versa [10, 11]. This revolutionary concept illustrated how competition between glucose and NEFA influences fuel utilisation by muscle, independent of hormonal influences. Details of the cellular basis for the Randle cycle have evolved over time. It was originally proposed that NEFA inhibit glycolysis, but subsequent studies have revealed that glucose transport is primarily affected [12]. In the last two decades it has been elucidated that NEFA affect early steps in the insulin signalling pathway, inhibiting tyrosine phosphorylation of the insulin receptor [13], and downstream IRS-1-associated phosphoinositide 3-kinase activity [12]. Regardless of the molecular underpinnings of the Randle cycle, its existence has profound implications for insulin signalling and the development of diabetes. It has been postulated that chronically elevated NEFA explains the propensity for diabetes in the obese [14]. Counter-intuitively, however, adiposity does not consistently increase plasma NEFA [15, 16]. Therefore, perhaps other factors leading to chronic NEFA elevation mediate risks of diabetes.

In this issue of Diabetologia, Broussard and colleagues [17] present their findings on the impact of sleep restriction on 24 h metabolic profiles, including NEFA. Nineteen healthy men were allowed to sleep a full 8.5 h per night or were restricted to 4.5 h of sleep per night for four consecutive nights. These two sleep protocols were performed in random order, with an intervening period of >4 weeks. On the third day of each protocol, detailed metabolic profiles were obtained, including plasma cortisol, noradrenaline (norepinephrine), glucose, insulin and NEFA. On the fourth morning of each protocol, insulin sensitivity was tested using an IVGTT. The authors found an increase in NEFA of about 15–30% during sleep restriction compared with normal sleep, with most of the increase occurring between 04:00 hours and 09:00 hours. In addition, sleep restriction increased nocturnal growth hormone, noradrenaline and cortisol. Morning insulin sensitivity was impaired and correlated with the extent of NEFA elevation during the night, but did not correlate with other hormonal changes. These findings suggest that NEFA may mediate insulin resistance during acute sleep restriction.

About one-third of human existence is spent asleep, such that even minor metabolic shifts that transpire during this period may have major chronic health implications. The authors should be commended for completing a rigorous study of metabolic profiles during 24 h of sleep restriction. Using this methodology they have shown how NEFA might be a mechanism by which sleep restriction induces insulin resistance. However, as the authors themselves point out, associated increases in counter-regulatory signals from growth hormone, cortisol and noradrenaline may have induced insulin resistance, either independently or in combination. For example, cortisol may directly stimulate lipolysis [18] or sensitise adipocytes to lipolytic effects of catecholamines and growth hormone [19]. To definitively link NEFA to sleep restriction-induced insulin resistance, studies involving lipolysis inhibitors and/or muscle insulin signalling would be highly informative. Another limitation is whether voluntary sleep restriction or insomnia (unwanted sleep restriction) elicits the same metabolic changes under real-world conditions.

Is a 15–30% increase in plasma NEFA for 5 h clinically significant? With regard to the duration of NEFA elevation, the answer is yes. After 3 h of lipid infusions in healthy volunteers, rates of glucose disappearance decreased by 55% [20]. Conversely, acutely lowering plasma NEFA with acipimox improved insulin sensitivity within 12 h [21]. In terms of the 15–30% increase, the answer is ‘perhaps’. Belfort et al [22] clamped plasma NEFA for 4 h at 58%, 184% and 283% above baseline and showed that glucose disposal rates fell by 22%, 30% and 34%, respectively. Vastus lateralis muscle IRS-1 phosphorylation and PI3 activity were reduced even at the lowest NEFA target. Qualitatively similar findings occurred with lipid infusions lasting several days [23]. Taken together, these studies indicate that physiological variations in plasma NEFA levels can dynamically affect glucose disposal and insulin receptor signalling. In their study, Broussard et al [17] detected insulin resistance in the morning following the fourth night of sleep restriction using an IVGTT. In a parallel manner, 1 day earlier in their experiment, glucose and insulin responses to breakfast were altered with sleep restriction. Interestingly, the metabolic responses to subsequent meals normalised, suggesting that insulin resistance was limited to the morning hours. It is not clear whether chronic sleep restriction would continue to elicit this pattern of insulin resistance, nor if insulin resistance of this nature can lead to diabetes in susceptible individuals.

This study opens the door to several additional intriguing questions and hypotheses. First, why is there such heterogeneity in the NEFA response to sleep restriction (see Fig. 5b in [17]) and could this heterogeneity explain susceptibility to metabolic consequences? Second, what is the origin, metabolic fate and composition of the NEFA mobilised during sleep restriction? Fatty acid species are differentially mobilised during lipolysis according to their structure [24], and degrees of fatty acid saturation and chain length induce variable degrees of insulin resistance [25, 26]. Third, could dysregulation of NEFA metabolism represent a common pathway linking several sleep disorders to the metabolic syndrome? For example, nocturnal [27] and morning [28] NEFA are increased in individuals with obstructive sleep apnoea. Inconsistent sleep patterns due to shift work or circadian rhythm disorders might cause sporadic surges in lipolytic hormones [29, 30]. Both sleep loss and obstructive sleep apnoea are associated with an overlapping set of cardio-metabolic disorders [31], and NEFA elevations are implicated in these same pathologies [32, 33, 34, 35].

As we seek the answers to these questions, we should not lose sight of the proverbial forest through the trees: the evidence is abundantly clear that sleep loss constitutes a common modifiable risk factor for diabetes. The greater mystery may be why clinicians do not routinely ask their patients about sleep.


Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

JCJ and VYP were both responsible for drafting the article and revising it critically for important intellectual content. Both authors approved the version to be published.


  1. 1.
    Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E (2005) Sleep loss: a novel risk factor for insulin resistance and type 2 diabetes. J Appl Physiol 99:2008–2019CrossRefPubMedGoogle Scholar
  2. 2.
    Beihl DA, Liese AD, Haffner SM (2009) Sleep duration as a risk factor for incident type 2 diabetes in a multiethnic cohort. Ann Epidemiol 19:351–357CrossRefPubMedGoogle Scholar
  3. 3.
    Knutson KL (2010) Sleep duration and cardiometabolic risk: a review of the epidemiologic evidence. Best Pract Res Clin Endocrinol Metab 24:731–743CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Spiegel K, Leproult R, Van Cauter E (1999) Impact of sleep debt on metabolic and endocrine function. Lancet 354:1435–1439CrossRefPubMedGoogle Scholar
  5. 5.
    Taheri S, Lin L, Austin D, Young T, Mignot E (2004) Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Med 1:e62CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Cappuccio FP, Taggart FM, Kandala NB et al (2008) Meta-analysis of short sleep duration and obesity in children and adults. Sleep 31:619–626PubMedCentralPubMedGoogle Scholar
  7. 7.
    St-Onge MP, Roberts AL, Chen J et al (2011) Short sleep duration increases energy intakes but does not change energy expenditure in normal-weight individuals. Am J Clin Nutr 94:410–416CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Spiegel K, Tasali E, Penev P, Van Cauter E (2004) 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 141:846–850CrossRefPubMedGoogle Scholar
  9. 9.
    Spaeth AM, Dinges DF, Goel N (2013) Effects of experimental sleep restriction on weight gain, caloric intake, and meal timing in healthy adults. Sleep 36:981–990PubMedCentralPubMedGoogle Scholar
  10. 10.
    Randle PJ, Garland PB, Hales CN, Newsholme EA (1963) The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–789CrossRefPubMedGoogle Scholar
  11. 11.
    Randle PJ (1998) Regulatory interactions between lipids and carbohydrates: the glucose fatty acid cycle after 35 years. Diabetes Metab Rev 14:263–283CrossRefPubMedGoogle Scholar
  12. 12.
    Dresner A, Laurent D, Marcucci M et al (1999) Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 103:253–259CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Kashyap S, Belfort R, Gastaldelli A et al (2003) A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 52:2461–2474CrossRefPubMedGoogle Scholar
  14. 14.
    Boden G (1998) Free fatty acids (FFA), a link between obesity and insulin resistance. Front Biosci J Virtual Lib 3:d169–d175Google Scholar
  15. 15.
    Karpe F, Dickmann JR, Frayn KN (2011) Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 60:2441–2449CrossRefPubMedCentralPubMedGoogle Scholar
  16. 16.
    Johns I, Goff L, Bluck LJ et al (2014) Plasma free fatty acids do not provide the link between obesity and insulin resistance or beta-cell dysfunction: results of the Reading, Imperial, Surrey, Cambridge, Kings (RISCK) study. Diabet Med 31:1310–1315CrossRefPubMedGoogle Scholar
  17. 17.
    Broussard JL, Chapotot F, Abraham V, et al (2015) Sleep restriction increases free fatty acids in healthy men. Diabetologia. doi: 10.1007/s00125-015-3500-4
  18. 18.
    Xu C, He J, Jiang H et al (2009) Direct effect of glucocorticoids on lipolysis in adipocytes. Mol Endocrinol 23:1161–1170CrossRefPubMedGoogle Scholar
  19. 19.
    Macfarlane DP, Forbes S, Walker BR (2008) Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. J Endocrinol 197:189–204CrossRefPubMedGoogle Scholar
  20. 20.
    Boden G, Jadali F (1991) Effects of lipid on basal carbohydrate metabolism in normal men. Diabetes 40:686–692CrossRefPubMedGoogle Scholar
  21. 21.
    Santomauro AT, Boden G, Silva ME et al (1999) Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects. Diabetes 48:1836–1841CrossRefPubMedGoogle Scholar
  22. 22.
    Belfort R, Mandarino L, Kashyap S et al (2005) Dose-response effect of elevated plasma free fatty acid on insulin signaling. Diabetes 54:1640–1648CrossRefPubMedGoogle Scholar
  23. 23.
    Kashyap SR, Belfort R, Berria R et al (2004) Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes. Am J Physiol Endocrinol Metab 287:E537–E546CrossRefPubMedGoogle Scholar
  24. 24.
    Conner WE, Lin DS, Colvis C (1996) Differential mobilization of fatty acids from adipose tissue. J Lipid Res 37:290–298PubMedGoogle Scholar
  25. 25.
    Borkman M, Storlien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV (1993) The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids. N Engl J Med 328:238–244CrossRefPubMedGoogle Scholar
  26. 26.
    Han P, Zhang YY, Lu Y, He B, Zhang W, Xia F (2008) Effects of different free fatty acids on insulin resistance in rats. Hepatobiliary Pancreat Dis Int 7:91–96PubMedGoogle Scholar
  27. 27.
    Jun JC, Drager LF, Najjar SS et al (2011) Effects of sleep apnea on nocturnal free fatty acids in subjects with heart failure. Sleep 34:1207–1213PubMedCentralPubMedGoogle Scholar
  28. 28.
    Barcelo A, Pierola J, de la Pena M et al (2011) Free fatty acids and the metabolic syndrome in patients with obstructive sleep apnoea. Eur Respir J 37:1418–1423CrossRefPubMedGoogle Scholar
  29. 29.
    Cooper BG, White JE, Ashworth LA, Alberti KG, Gibson GJ (1995) Hormonal and metabolic profiles in subjects with obstructive sleep apnea syndrome and the acute effects of nasal continuous positive airway pressure (CPAP) treatment. Sleep 18:172–179PubMedGoogle Scholar
  30. 30.
    Van Cauter E (2000) Slow wave sleep and release of growth hormone. JAMA 284:2717–2718PubMedGoogle Scholar
  31. 31.
    Mesarwi O, Polak J, Jun J, Polotsky VY (2013) Sleep disorders and the development of insulin resistance and obesity. Endocrinol Metab Clin N Am 42:617–634CrossRefGoogle Scholar
  32. 32.
    Florian JP, Pawelczyk JA (2010) Non-esterified fatty acids increase arterial pressure via central sympathetic activation in humans. Clin Sci 118:61–69CrossRefGoogle Scholar
  33. 33.
    Zhang H, Dellsperger KC, Zhang C (2012) The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: an update. Basic Res Cardiol 107:237CrossRefPubMedGoogle Scholar
  34. 34.
    Sniderman AD, Cianflone K (1993) Substrate delivery as a determinant of hepatic apoB secretion. Arterioscler Thromb 13:629–636CrossRefPubMedGoogle Scholar
  35. 35.
    Pilz S, Marz W (2008) Free fatty acids as a cardiovascular risk factor. Clin Chem Lab Med 46:429–434CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Pulmonary and Critical Care MedicineJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations