Arlet Nedeltcheva

Impact of Sleep and Sleep Loss on Neuroendocrine and Metabolic Function

Background: Sleep exerts important modulatory effects on neuroendocrine function and glucose regulation. During the past few decades, sleep curtailment has become a very common behavior in industrialized countries. This trend toward shorter sleep times has occurred over the same time period as the dramatic increases in the prevalence of obesity and diabetes. Aims: This article will review rapidly accumulating laboratory and epidemiologic evidence indicating that chronic partial sleep loss could play a role in the current epidemics of obesity and diabetes. Conclusions: Laboratory studies in healthy young volunteers have shown that experimental sleep restriction is associated with a dysregulation of the neuroendocrine control of appetite consistent with increased hunger and with alterations in parameters of glucose tolerance suggestive of an increased risk of diabetes. Epidemiologic findings in both children and adults are consistent with the laboratory data.

Insufficient Sleep Undermines Dietary Efforts to Reduce Adiposity

BACKGROUND Sleep loss can modify energy intake and expenditure. OBJECTIVE To determine whether sleep restriction attenuates the effect of a reduced-calorie diet on excess adiposity. DESIGN Randomized, 2-period, 2-condition crossover study. SETTING University clinical research center and sleep laboratory. PATIENTS 10 overweight nonsmoking adults (3 women and 7 men) with a mean age of 41 years (SD, 5) and a mean body mass index of 27.4 kg/m² (SD, 2.0). INTERVENTION 14 days of moderate caloric restriction with 8.5 or 5.5 hours of nighttime sleep opportunity. MEASUREMENTS The primary measure was loss of fat and fat-free body mass. Secondary measures were changes in substrate utilization, energy expenditure, hunger, and 24-hour metabolic hormone concentrations. RESULTS Sleep curtailment decreased the proportion of weight lost as fat by 55% (1.4 vs. 0.6 kg with 8.5 vs. 5.5 hours of sleep opportunity, respectively; P = 0.043) and increased the loss of fat-free body mass by 60% (1.5 vs. 2.4 kg; P = 0.002). This was accompanied by markers of enhanced neuroendocrine adaptation to caloric restriction, increased hunger, and a shift in relative substrate utilization toward oxidation of less fat. LIMITATION The nature of the study limited its duration and sample size. CONCLUSION The amount of human sleep contributes to the maintenance of fat-free body mass at times of decreased energy intake. Lack of sufficient sleep may compromise the efficacy of typical dietary interventions for weight loss and related metabolic risk reduction. PRIMARY FUNDING SOURCE National Institutes of Health.

Exposure to recurrent sleep restriction in the setting of high caloric intake and physical inactivity results in increased insulin resistance and reduced glucose tolerance.

CONTEXT Epidemiological data indicate that reduced sleep duration is associated with increased incidence of type-2 diabetes. OBJECTIVE The aim of the study was to test the hypothesis that, when part of a Western-like lifestyle, recurrent bedtime restriction may result in decreased glucose tolerance and reduced insulin secretion and action. DESIGN AND SETTING We conducted a randomized crossover study at a university clinical research center and sleep research laboratory. PARTICIPANTS Eleven healthy volunteers (five females and six males) with a mean (+/-sd) age of 39 +/- 5 yr and body mass index of 26.5 +/- 1.5 kg/m(2) participated in the study. INTERVENTION The study included two 14-d periods of controlled exposure to sedentary living with ad libitum food intake and 5.5- or 8.5-h bedtimes. MAIN OUTCOME MEASURES Oral and iv glucose challenges were used to obtain measures of glucose tolerance, glucose effectiveness, insulin secretion, and insulin sensitivity at the end of each intervention. Secondary measures included circulating concentrations of the glucose counter-regulatory hormones, cortisol, GH, epinephrine, and norepinephrine. RESULTS Bedtime restriction reduced daily sleep by 122 +/- 25 min. Both study periods were associated with comparable weight gain; however, recurrent sleep restriction resulted in reduced oral glucose tolerance (2-h glucose value, 144 +/- 25 vs. 132 +/- 36 mg/dl; P < 0.01) and insulin sensitivity [3.3 +/- 1.1 vs. 4.0 +/- 1.6 (mU/liter)(-1) x min(-1); P < 0.03], and increased glucose effectiveness (0.023 +/- 0.005 vs. 0.020 +/- 0.005 min(-1); P < 0.04). Although 24-h cortisol and GH concentrations did not change, there was a modest increase in 24-h epinephrine and nighttime norepinephrine levels during the 5.5-h bedtime condition. CONCLUSIONS Experimental bedtime restriction, designed to approximate the short sleep times experienced by many individuals in Westernized societies, may facilitate the development of insulin resistance and reduced glucose tolerance.

Temporal Disorganization of Circadian Rhythmicity and Sleep-Wake Regulation in Mechanically Ventilated Patients Receiving Continuous Intravenous Sedation

OBJECTIVES Sleep is regulated by circadian and homeostatic processes and is highly organized temporally. Our study was designed to determine whether this organization is preserved in patients receiving mechanical ventilation (MV) and intravenous sedation. DESIGN Observational study. SETTING Academic medical intensive care unit. PATIENTS Critically ill patients receiving MV and intravenous sedation. METHODS Continuous polysomnography (PSG) was initiated an average of 2.0 (1.0, 3.0) days after ICU admission and continued ≥ 36 h or until the patient was extubated. Sleep staging and power spectral analysis were performed using standard approaches. We also calculated the electroencephalography spectral edge frequency 95% SEF₉₅, a parameter that is normally higher during wakefulness than during sleep. Circadian rhythmicity was assessed in 16 subjects through the measurement of aMT6s in urine samples collected hourly for 24-48 hours. Light intensity at the head of the bed was measured continuously. MEASUREMENTS AND RESULTS We analyzed 819.7 h of PSG recordings from 21 subjects. REM sleep was identified in only 2/21 subjects. Slow wave activity lacked the normal diurnal and ultradian periodicity and homeostatic decline found in healthy adults. In nearly all patients, SEF₉₅ was consistently low without evidence of diurnal rhythmicity (median 6.3 [5.3, 7.8] Hz, n = 18). A circadian rhythm of aMT6s excretion was present in most (13/16, 81.3%) patients, but only 4 subjects had normal timing. Comparison of the SEF₉₅ during the melatonin-based biological night and day revealed no difference between the 2 periods (P = 0.64). CONCLUSIONS The circadian rhythms and PSG of patients receiving mechanical ventilation and intravenous sedation exhibit pronounced temporal disorganization. The finding that most subjects exhibited preserved, but phase delayed, excretion of aMT6s suggests that the circadian pacemaker of such patients may be free-running.

Sleep disturbances, daytime sleepiness, and quality of life in adults with growth hormone deficiency.

CONTEXT Low energy and fatigue are frequent complaints in subjects with GH deficiency (GHD). Because interrelations between sleep and GH regulation are well documented, these complaints could partly reflect alterations of sleep quality. OBJECTIVE The objective of the study was to determine objective and subjective sleep quality and daytime sleepiness in adult GHD patients. SUBJECTS Thirty patients, aged 19-74 yr, with untreated GHD (primary pituitary defects confirmed or likely in 26 patients, hypothalamic origin in four patients), and 30 healthy controls individually matched for gender, age, and body mass index participated in the study. Patients with associated pituitary deficiencies (n = 28) were on hormonal replacement therapy. METHODS Polygraphic sleep recordings, assessment of Pittsburgh Sleep Quality Index, and Quality of Life Assessment for GHD in Adults were measured. RESULTS Irrespective of etiology, GHD patients had a Pittsburgh Sleep Quality Index score above the clinical cutoff for poor sleep and lower Quality of Life Assessment for GHD in Adults scores than controls, with tiredness being the most affected domain. Patients with pituitary GHD spent more time in slow-wave sleep (SWS) and had a higher intensity of SWS than their controls. Among these patients, older individuals obtained less total sleep than controls, and their late sleep was more fragmented. Contrasting with pituitary GHD, the four patients with hypothalamic GHD had lower intensity of SWS than their controls. CONCLUSIONS GHD is associated with sleep disorders that may be caused by specific hormonal alterations as well as with poor subjective sleep quality and daytime sleepiness. Disturbed sleep is likely to be partly responsible for increased tiredness, a major component of quality of life in GHD.

Effects of Sleep Restriction on Glucose Control and Insulin Secretion During Diet‐Induced Weight Loss

Insufficient sleep is associated with changes in glucose tolerance, insulin secretion, and insulin action. Despite widespread use of weight‐loss diets for metabolic risk reduction, the effects of insufficient sleep on glucose regulation in overweight dieters are not known. To examine the consequences of recurrent sleep restriction on 24‐h blood glucose control during diet‐induced weight loss, 10 overweight and obese adults (3F/7M; mean (s.d.) age 41 (5) years; BMI 27.4 (2.0) kg/m2) completed two 14‐day treatments with hypocaloric diet and 8.5‐ or 5.5‐h nighttime sleep opportunity in random order 7 (3) months apart. Oral and intravenous glucose tolerance test (IVGTT) data, fasting lipids and free fatty acids (FFA), 24‐h blood glucose, insulin, C‐peptide, and counter‐regulatory hormone measurements were collected after each treatment. Participants had comparable weight loss (1.0 (0.3) BMI units) during each treatment. Bedtime restriction reduced sleep by 131 (30) min/day. Recurrent sleep curtailment decreased 24‐h serum insulin concentrations (i.e., enhanced 24‐h insulin economy) without changes in oral glucose tolerance and 24‐h glucose control. This was accompanied by a decline in fasting blood glucose, increased fasting FFA, which suppressed normally following glucose ingestion, and lower total and low‐density lipoprotein cholesterol concentrations. Sleep‐loss‐related changes in counter‐regulatory hormone secretion during the IVGTT limited the utility of the test in this study. In conclusion, sleep restriction enhanced 24‐h insulin economy without compromising glucose homeostasis in overweight individuals placed on a balanced hypocaloric diet. The changes in fasting blood glucose, insulin, lipid and FFA concentrations in sleep‐restricted dieters resembled the pattern of human metabolic adaptation to reduced carbohydrate availability.

Impact of GH replacement therapy on sleep in adult patients with GH deficiency of pituitary origin

OBJECTIVES We previously reported that adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect, compared with healthy controls individually matched for age, gender, and BMI, have more slow-wave sleep (SWS) and higher delta activity (a marker of SWS intensity). Here, we examined the impact of recombinant human GH (rhGH) therapy, compared with placebo, on objective sleep quality in a subset of patients from the same cohort. DESIGN Single-blind, randomized, crossover design study. METHODS Fourteen patients with untreated GHD of confirmed or likely pituitary origin, aged 22-74 years, participated in the study. Patients with associated hormonal deficiencies were on appropriate replacement therapy. Polygraphic sleep recordings, with bedtimes individually tailored to habitual sleep times, were performed after 4 months on rhGH or placebo. RESULTS Valid data were obtained in 13 patients. At the end of the rhGH treatment period, patients had a shorter sleep period time than at the end of the placebo period (479±11 vs 431±19 min respectively; P=0.005), primarily due to an earlier wake-up time, and a decrease in the intensity of SWS (delta activity) (559±125 vs 794±219 μV(2) respectively; P=0.048). CONCLUSIONS Four months of rhGH replacement therapy partly reversed sleep disturbances previously observed in untreated patients. The decrease in delta activity associated with rhGH treatment adds further evidence to the hypothesis that the excess of high-intensity SWS observed in untreated pituitary GHD patients is likely to result from overactivity of the hypothalamic GHRH system due to the lack of negative feedback inhibition by GH.

Effetti della terapia sostitutiva con GH sul sonno nei pazienti adulti con deficit di GH di origine ipofisaria

L.L. Morselli, A. Nedeltcheva, R. Leproult, K. Spiegel, E. Martino, J.J. Legros, R.E. Weiss, J. Mockel, E. Van Cauter, G. Copinschi Eur J Endocrinol 2013; 168: 763-770 La secrezione ipofisaria di GHRH non solo regola la produzione di GH da parte delle cellule somatotrope dell’ipofisi, ma influenza anche il sonno. In modo particolare, l’attività di GHRH è legata all’induzione degli stadi più profondi del sonno, caratterizzati dalla presenza all’elettroencefalogramma delle tipiche onde delta di ampio voltaggio e bassa frequenza (0,75-4 Hz). L’assenza di feedback negativo sulla regolazione dell’attività dei neuroni ipotalamici che rilasciano GHRH, come avviene nel deficit di GH (GHD) di origine ipofisaria, potrebbe quindi tradursi in una marcata stimolazione del sonno non REM profondo o sonno a “onde lente”. I pazienti con GHD non trattati riferiscono spesso sonnolenza diurna e una generale perdita delle proprietà rigeneranti del sonno, con conseguenti ripercussioni negative sulla qualità di vita. Recenti studi dimostrano infatti che il sonno in pazienti con GHD legato a cause ipofisarie si presenta frammentato, costituito da una attività delta o slowwave activity (SWA) preponderante rispetto ai soggetti sani. Lo scopo di questo studio è stato quello di valutare se la somministrazione di rhGH per 4 mesi fosse in grado di modificare l’eccessiva presenza di sonno ad onde lente nei pazienti adulti con GHD ipofisario. Lo studio ha coinvolto 13 pazienti adulti (età 22-77 anni) con diagnosi certa o presunta di GHD di origine ipofisaria formulata in base al riscontro di valori di GH <3 μg/l in risposta all’insulin tolerance test (ITT). I pazienti venivano suddivisi in maniera randomizzata in un gruppo che riceveva placebo e in uno a cui veniva somministrato rhGH. Al termine di 4 mesi di trattamento venivano acquisite informazioni sulla durata e sulla struttura del sonno nei due gruppi mediante registrazione polisonnografica e attraverso un sensore di movimento applicato al polso (wrist actigraphy). La somministrazione di rhGH ha determinato una riduzione della durata totale di sonno rispetto al placebo (479±11 vs 431±19 minuti; p=0,005). Questo dato riflette principalmente la tendenza al risveglio anticipato nei pazienti trattati con GH rispetto al placebo. Il trattamento ha provocato una riduzione del 27% dell’attività ad onde lente (stadio III e IV NREM) statisticamente non significativa. Tuttavia l’attività delta registrata durante le prime 6 ore di sonno è diminuita del 30% al termine del trattamento con rhGH rispetto al placebo (p=0,048). I dati polisonnografici registrati concordavano con le sensazioni riportate dai pazienti al termine del periodo di trattamento, con una riduzione del sonno (differenza di 24 minuti; p=0,002) e un risveglio anticipato (differenza di 46 minuti; p=0,007) rispetto al placebo. Questo studio, sebbene sia stato condotto in un campione esiguo di soggetti e per la maggior parte di età superiore ai 40 anni (l’attività delta tende a ridursi fisiologicamente con l’avanzare dell’età), dimostra che il trattamento con rhGH per 4 mesi può invertire alcuni dei disturbi del sonno osservati nei pazienti adulti con GHD. Questi risultati, inoltre, aggiungono una serie di prove del ruolo centrale svolto dal GHRH nel modulare la qualità del sonno nell’uomo.