Research Review By Christopher Howard©

Date Posted:

November 2010

Study Title:

Exposure to Recurrent Sleep Restriction in the Setting of High Caloric Intake and Physical Inactivity Results in Increased Insulin Resistance and Reduced Glucose Tolerance

Authors:

Nedeltcheva AV, Kessler L, Imperial J, Penev PD

Author's Affiliations:

Department of Medicine, and General Clinical Research Center, University of Chicago, USA.

Publication Information:

Journal of Clinical Endocrinology & Metabolism 2009; 94(9): 3242-3250.

Background Information:

Type 2 diabetes is becoming increasingly common in the modern world, mostly due to overeating and lack of physical activity (1). More recently, though, it is believed that sleep restriction may be a risk factor in the development of type 2 diabetes and other metabolic disorders. Many Americans sleep fewer than 6 hours per night (2) and such individuals are at increased risk of developing type 2 diabetes (3).

Few controlled studies have examined the relationship between sleep restriction and insulin secretion and action in the development of type 2 diabetes. Of the studies that have examined sleep deprivation, several limitations have been noted:
  1. previous studies have restricted sleep to abnormally low levels, often less than 4 hours per night,
  2. previous studies have examined only the acute (< 7 days) effects of sleep deprivation on carbohydrate metabolism,
  3. the diets of study participants were not documented sufficiently,
  4. most of the study participants were lean, male volunteers, not middle-aged men and women.
This study examined the effects of sleep restriction of middle-aged adults to 5.5 hours per night on glucose tolerance and insulin secretion and sensitivity. In addition, this study measured the effects of sleep deprivation on cortisol, growth hormone, epinephrine, and norepinephrine.

The subjects in this study were provided ad libitum access to palatable food and were required to remain sedentary throughout the duration of the study. This makes sense because current Western lifestyles are plagued with inactivity and overeating.

Pertinent Results:

Sleep Duration:
  • As sleep time changed from 8.5 to 5.5 h, subjects went to bed later (12:30am vs. 11:16pm) and got out of bed earlier (6:02am vs. 7:42am). Mean sleep duration was reduced from 7hours 13 minutes with 8.5 hours of sleep to 5 hours 11 minutes with 5.5 hours of sleep (P < 0.001).
Glucose Tolerance, Beta-cell Function, Insulin Sensitivity:
  • There were no differences in fasting glucose and insulin concentrations between the two sleep conditions.
  • 2 hour glucose values and the area under the 3 hour Oral Glucose Tolerance Test curve for glucose were significantly increased at the end of the bedtime restriction period. This was not the case for insulin.
  • Sleep deprivation resulted in reduced insulin sensitivity and higher glucose effectiveness at basal insulin concentration and at zero insulin.
  • There were no statistically significant differences in the acute insulin response to glucose and disposition index between the two bedtime conditions.
Cortisol:
  • The area under the 24-h curve of serum cortisol was similar between the 5.5-and 8.5-h bedtime conditions (P = 0.55).
  • Measured profiles had comparable peak, trough, daytime, and nighttime cortisol concentrations.
  • Compared with the 8.5-h bedtime period, the best-fit 24-h cortisol curves at the end of the restricted sleep condition tended to have lower acrophase (P = 0.058), similar nadir, and significantly decreased amplitude (P = 0.014).
  • The time of nadir during sleep deprivation was delayed from 12:27am to 1:38am (P = 0.012) and acrophase advanced from 7:49am to 7:05am (P = 0.012).
  • The 5.5-h bedtime condition was accompanied by a small increase in cortisol concentrations between 8:00pm and 10:00pm (P = 0.01). However, this difference did not have a measurable effect on the duration of the corresponding “quiescent periods”.
  • Serum cortisol concentrations declined progressively during the IVGTT period of the 8.5 hous of sleep condition.
  • During the 5.5 hours of sleep condition a significant rise in cortisol concentrations during the third and fourth hours (P = 0.02) after the IV-glucose challenge was observed.
Growth Hormone:
  • There were no statistically significant differences in 24-h mean, daytime, and nighttime GH concentrations between groups.
  • Sleep restriction was associated with lower GH concentrations during the first 4 h of the assigned bedtime period (P = 0.04). This effect occurred mainly in male subjects and was not apparent in female participants.
  • There were no significant differences in GH levels during the IVGTT period between the two sleep conditions. Hormone concentrations remained low during the first 2 h of the test and increased significantly during the third (P = 0.001) and fourth hours (P = 0.021) after the IV glucose challenge.
Plasma Catecholamines:
  • Integrated daytime (P = 0.027), nighttime (P = 0.046), and 24-h epinephrine concentrations (P=0.042) were higher during 5.5 hours of sleep compared with 8.5 hours of sleep.
  • Epinephrine levels increased during the third and fourth hours of the IVGTT period during both sleep conditions (P =0.001), but reached significantly higher levels at the end of the 5.5 hours of sleep condition (P = 0.05).
  • Recurrent sleep restriction was accompanied by increased overnight (P = 0.043), but not daytime or 24-h norepinephrine levels.
  • There were no statistically detectable differences in plasma norepinephrine concentrations during the IVGTT period between the two bedtime conditions.

Clinical Application & Conclusions:

The key finding of this study was that continual sleep restriction to 5.5 hours per night combined with overeating and inactivity, resulted in higher 2-h OGTT glucose levels and an increased area under the OGTT glucose curve, indicating decreased oral glucose tolerance.

In addition, sleep restriction was shown to lead to reduced insulin sensitivity, a known factor in diabetes. Sleep restriction also did not result in significantly increased levels of growth hormone or cortisol, but did lead to increased levels of catecholamines overnight (11:00pm – 9:00am).

Either way you look at it, sleep restriction is not recommended for optimal health. It is understandable that in today’s busy world, achieving 8 hours of sleep per night is not always possible. However, the results of this study should encourage everyone to try, if for no other reason than to reduce risk of type 2 diabetes.

Study Methods:

Subjects:
  • Eleven sedentary adults (six females, five males) with an average age of 39 +/- 5 years, body mass index 26.5 +/- 1.5 kg/m2, and self reported sleep duration of 7.6 +/- 0.7 hours/day participated in this study.
Study Protocol:
  • Each subject completed two 14-d study periods with sedentary activity, ad libitum food intake, and scheduled bedtimes of 5.5 or 8.5 hours per night in random order at least 3 months apart.
  • Starting at 8:00pm on the last day of each experimental condition, participants were transferred to the General Clinical Research Center for 48 hours of additional testing. During the last 24 hours of this period, subjects remained at bed rest and blood was sampled every 30 min. However, for the first hour after meals and the first 2 hours of scheduled bedtime, blood was collected every 15 min.
  • Bedtimes were maintained at 5.5 or 8.5 hours according to the assigned experimental condition. In the morning of the first day, after a 14-hour overnight fast, study participants underwent a 3-h oral glucose tolerance test (OGTT) as follows: baseline blood samples were collected at -15 and 0 min for measurements of glucose and insulin, 75g glucose was administered orally, and additional samples were collected at 30, 60, 90, 120, 150, and 180 min after the glucose challenge.
  • An IV glucose tolerance test (IVGTT) was performed under similar settings starting at 9:00am on the second day. The IVGTT was incorporated in the ongoing sequence of 24-h blood sampling as follows: a 0.3 g/kg IV glucose bolus was given after the 9:00am blood collection, followed by a 0.03 U/kg bolus of regular insulin 20 min later; samples were taken 2, 3, 4, 6, 8, 10, 12, 14, 16, 19, 22, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, and 180 min after the glucose bolus; and the usual 24-h blood drawing sequence was resumed at 1230pm. Identical carbohydrate-rich meals were served at 2:00pm and 7:00pm on both testing days.
Sleep Monitoring:
  • Sleep was recorded polygraphically and scored according to standard clinical criteria. Total sleep time was calculated as the sum of all sleep epochs.
Assays:
  • Plasma glucose was measured at the bedside in whole venous blood. Serum insulin, total cortisol, and GH concentrations were measured using human chemiluminescent enzyme immunoassays. Due to limitations in sample volume, plasma epinephrine and norepinephrine were measured in seven of the 11 study participants.
Data Analysis:
  • Fasting glucose and insulin concentrations were calculated as the average of the -15 and 0-min OGTT readings. The 120-min glucose concentration provided a clinically relevant measure of oral glucose tolerance. The areas under the 3-h OGTT glucose and insulin curves were calculated using the trapezoidal rule. IVGTT-based estimates of insulin sensitivity (SI), glucose effectiveness at basal insulin concentration (SG), glucose effectiveness at zero insulin (GEZI), and the acute insulin response to glucose (AIRG) were derived by minimal model analysis. To assess Beta-cell compensation for the degree of insulin resistance, the disposition index, DI, was calculated as the product of AIRG and SI.
  • In addition to comparing the 24-h hormone concentrations during each sleep condition, cortisol, GH, epinephrine, and norepinephrine levels were analyzed during the following time intervals: 1) 9:00am – 11:00pm, daytime period; 2) 11:00pm –9:00am, overnight period; and 3) 9:00am –1:00pm, post-IV-glucose period.
  • A best-fit regression curve based on the 24-h concentrations of each subject was used to characterize the diurnal rhythm in cortisol secretion. The maximum and minimum of each regression curve defined the acrophase and nadir of the 24-h rhythm. Amplitude was equal to half the difference between acrophase and nadir. The “quiescent period” of overnight cortisol secretion was the time when cortisol concentrations remained below 5 micrograms/dl.
Statistics:
  • Measures of insulin secretion and sensitivity and glucose tolerance at the end of each study were compared using generalized estimating equation regression models with bedtime condition (5.5 vs. 8.5 h), order of treatment (initial vs. crossover study), and final body weight as time-varying factors. Paired t-tests were used for exploratory comparisons of cortisol and GH levels between the two sleep conditions. Plasma catecholamine measurements were compared using the Wilcoxon paired sign rank test. ANOVA with bedtime condition and post-IV-glucose time (four consecutive 1-h intervals between 9:00am and 1:00pm) as repeated measures was used to explore the hormonal changes after the IV-glucose challenge. Statistical analyses were performed using SPSS, version 16.0.

Study Strengths / Weaknesses:

The authors noted that the accuracy of IVGTT-based estimates of glucose effectiveness has not been determined for sleep-deprived individuals. This could be a huge factor in the accuracy of the outcomes of the study. In addition, diet was not controlled in this study.

Yes, subjects were allowed to consume as much as they wanted, however when subjects are restricted from sleep, they are awake longer and therefore have more time to eat than those who sleep longer. It would have been preferable to have data regarding how much food was consumed and at what times and macronutrient distributions among subject groups.

With the above limitations in mind, it is important to note that the authors did try to examine as many of the effects of sleep restriction on type 2 diabetes risk as possible. The inclusion of data on cortisol, growth hormone, and plasma catecholamines was very important and useful. In addition, it is important that the subjects were middle-aged men and women, as most studies examine young and healthy men and women. Most people in a state of sleep restriction are middle-aged, so the results of this study are very applicable.

Additional References:

  1. Zimmet P, Alberti KG, Shaw J 2001 Global and societal implications of the diabetes epidemic. Nature 414:782–787.
  2. Basner M, FombersteinKM,Razavi FM, Banks S, William JH, Rosa RR, Dinges DF 2007 American time use survey: sleep time and its relationship to waking activities. Sleep 30:1085–1095.
  3. Mallon L, Broman JE, Hetta J 2005 High incidence of diabetes in men with sleep complaints or short sleep duration: a 12-year follow-up study of a middle-aged population. Diabetes Care 28:2762 – 2767.