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. 2021 May 27;106(9):e3436–e3448. doi: 10.1210/clinem/dgab375

Clamping Cortisol and Testosterone Mitigates the Development of Insulin Resistance during Sleep Restriction in Men

Peter Y Liu 1,2,✉, Darian Lawrence-Sidebottom 3,4, Katarzyna Piotrowska 1,1, Wenyi Zhang 1,1, Ali Iranmanesh 5, Richard J Auchus 6,7, Johannes D Veldhuis 8, Hans P A Van Dongen 3,9
PMCID: PMC8660069  PMID: 34043794

Abstract

Context

Sleep loss in men increases cortisol and decreases testosterone, and sleep restriction by 3 to 4 hours/night induces insulin resistance.

Objective

We clamped cortisol and testosterone and determined the effect on insulin resistance.

Methods

This was a randomized double-blind, in-laboratory crossover study in which 34 healthy young men underwent 4 nights of sleep restriction of 4 hours/night under 2 treatment conditions in random order: dual hormone clamp (cortisol and testosterone fixed), or matching placebo (cortisol and testosterone not fixed). Fasting blood samples, and an additional 23 samples for a 3-hour oral glucose tolerance test (OGTT), were collected before and after sleep restriction under both treatment conditions. Cytokines and hormones were measured from the fasting samples. Overall insulin sensitivity was determined from the OGTT by combining complementary measures: homeostasis model assessment of insulin resistance of the fasting state; Matsuda index of the absorptive state; and minimal model of both fasting and absorptive states.

Results

Sleep restriction alone induced hyperinsulinemia, hyperglycemia, and overall insulin resistance (P < 0.001 for each). Clamping cortisol and testosterone alleviated the development of overall insulin resistance (P = 0.046) and hyperinsulinemia (P = 0.014) by 50%. Interleukin-6, high-sensitivity C-reactive protein, peptide YY, and ghrelin did not change, whereas tumor necrosis factor-α and leptin changed in directions that would have mitigated insulin resistance with sleep restriction alone.

Conclusion

Fixing cortisol-testosterone exposure mitigates the development of insulin resistance and hyperinsulinemia, but not hyperglycemia, from sustained sleep restriction in men. The interplay between cortisol and testosterone may be important as a mechanism by which sleep restriction impairs metabolic health.

Keywords: insulin resistance, hyperinsulinemia, hyperglycemia, dual hormone clamp, cytokines, sleep loss

Despite growing recognition that adequate sleep is required for healthy living (1, 2), about 20% of the US population continues to sleep insufficiently (3-5). Across the lifespan, the accumulation of sleep loss may be substantial, and epidemiologic data indicate that this contributes to metabolic ill-health (1-3). Accordingly, there has been strong advocacy for community-directed measures to promote and prioritize sufficient sleep (5-7). However, large portions of the population continue to be deprived of sleep due to work demands, medical conditions, or lifestyle (4). To prevent the adverse metabolic effects of sleep restriction in these groups, targeted countermeasure approaches are needed that do not rely solely on supplementation of sleep. Understanding the mechanisms by which sleep loss leads to adverse metabolic outcomes would allow such targeted methods to be developed.

Randomized, controlled studies of sleep restriction have shown that reducing sleep by 3 to 4 hours/night for 4 to 14 consecutive nights reduces insulin sensitivity by 15% to 25% and thus produces insulin resistance (1). When insulin resistance worsens, pancreatic beta cell function can sometimes initially improve but ultimately fails, resulting in diminished pancreatic response to hyperglycemia. This initial step of insulin resistance thus sequentially leads to hyperinsulinemia, hyperglycemia, and the development of prediabetes and type 2 diabetes mellitus (T2DM). Indeed, epidemiological studies have shown that sleep restriction increases the risk of development of insulin resistance, prediabetes, and T2DM (2)—diseases that affect over 100 million Americans at an annual cost that exceeds $200 billion (8).

Potential mechanisms underlying the development of insulin resistance from sleep restriction include chronic inflammation, changes in metabolically active hormones secreted from the gastrointestinal and adipose tissues, and alterations in testosterone and cortisol. Inflammation has long been considered a putative mediator in the development of insulin resistance (9). Epidemiological studies have shown that increases in high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) predict future cardiovascular events, hypertension, obesity, and T2DM (10). Certain epidemiological studies have also linked shorter sleep duration with higher hs-CRP and IL-6, as well as TNFα (10).

The gastrointestinal and adipose tissues are major sites for the absorption and storage of nutrients, and hence of whole-body metabolism. Hormones that are secreted by gastrointestinal and adipose tissues are therefore potential signals that could be important for metabolic function and dysfunction, including the development of insulin resistance (11-13). Ghrelin and peptide YY (PYY), hormones that are principally secreted by the gut, and the adipokine leptin, have each been shown to directly influence insulin resistance (14-16). Cross-sectional and interventional studies have also indicated that these particular hormones may be altered by sleep restriction (2, 17). Accordingly, ghrelin, PYY, and leptin are potential mediators linking sleep restriction with the development of insulin resistance.

Cortisol and testosterone are the major catabolic and anabolic signals in men, respectively, and the hypothalamo-pituitary adrenal and hypothalamo-pituitary-testicular axes in which these hormones play a central role are intertwined in their regulation (1). Converging lines of evidence implicate cortisol and testosterone signaling to be important potential mechanisms by which insulin resistance may occur. Sleep loss prevents the usual fall in cortisol that occurs during the late afternoon/early evening (18-21), but it has variable effects in the morning which may be due to confounding by the cortisol wakening response (22). Preventing the fall in late afternoon/early evening cortisol by administering glucocorticoids to bolster cortisol levels induces insulin resistance (23-25). Furthermore, hypercortisolemia causes hepatic and peripheral insulin resistance through post-receptor mechanisms (26, 27) that are underpinned by distinct molecular processes (28). Specifically, glucocorticoid action in the liver and fat is responsible for hyperglycemia, hyperlipidemia, and release of free fatty acids—and therefore metabolic processes intimately associated with insulin action (29).

In addition, almost all studies show that sleep loss decreases daytime testosterone (21, 30-40), including our study showing that this occurs irrespective of age group (21). However, some studies that have measured testosterone at a single time point have not observed this reduction (1, 41). Randomized controlled trials show that testosterone treatment increases insulin sensitivity in men at risk for T2DM (42, 43), prevents the development of T2DM and improves glycemic control in men with T2DM (44), and directly regulates pathways responsible for skeletal muscle glucose metabolism (45). Accordingly, the mechanistic pathways linking cortisol and testosterone to insulin resistance are present, but whether sleep restriction acts through these pathways to trigger insulin resistance remains to be evaluated in the human (18-21, 30, 32, 46-49).

Here we investigated the role of cortisol and testosterone signaling in the development of insulin resistance caused by sleep restriction by means of a novel dual hormonal clamp intervention to fix cortisol and testosterone exposure. In a highly controlled, in-laboratory sleep restriction protocol (Fig. 1) with controlled diet, healthy young men underwent 1 night of 10 hours baseline sleep (22:00–08:00) followed by 4 consecutive nights where sleep was restricted to a 4-hour opportunity (01:00–05:00). This pattern was repeated on 2 separate occasions with different treatment conditions, in randomized order: (a) a condition with dual cortisol/testosterone clamp during the sleep restriction days, with ketoconazole to block endogenous steroidogenesis and simultaneous addback of oral hydrocortisone and transdermal testosterone gel at replacement doses recognized to maintain blood cortisol and testosterone concentrations at population mid-physiological levels (50-52); or (b) a matching placebo condition (ie, no clamp) where cortisol and testosterone were not fixed.

Figure 1.

Figure 1.

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Randomized, placebo-controlled, crossover, dual clamp study design.

In both conditions, after the baseline night and after the fourth sleep-restricted night, a 3-hour oral glucose tolerance test (OGTT) with 75 g glucose and intensive blood sampling (23 samples) was performed. From the OGTT samples, insulin sensitivity was assessed based on a triad of complementary methods: homeostasis model assessment of insulin resistance (HOMA-IR) of the fasting state; Matsuda index (Mi) of the absorptive state; and insulin sensitivity (Si) from minimal model of both the fasting and absorptive states. We also determined hyperinsulinemia assessed as insulin area under the curve (AUC), hyperglycemia assessed as glucose AUC; as well as total pancreatic beta cell responsivity to glucose (total phi) and pancreatic response to insulin resistance (disposition index) from minimal model of the OGTT (see supplementary materials). Additionally, key proinflammatory markers (hs-CRP, IL-6, and TNF-α) and metabolically active hormones (ghrelin, PYY, leptin) were measured from blood collected while fasting in the morning, immediately before the OGTT. By comparing the effects of sleep restriction between the 2 treatment conditions, we assessed whether the dual clamp dampened the development of insulin resistance, thereby signifying the mechanism and degree by which the interplay between cortisol and testosterone mediates the development of insulin resistance; and to what extent inflammation and metabolically active gut and fat hormones may have played a role.

Methods

Participants

Thirty-four healthy, drug- and medication-free young adult men, aged 33.3 ± 6.4 years (mean ± SD), with body mass index (BMI) 25.6 ± 2.6 kg/m2 completed the study in the sleep laboratory of the Clinical and Translational Research Center of the Lundquist Institute at Harbor UCLA Medical Center. Health status was determined by extensive medical history, and physical, psychological, and laboratory examination, which included 12-lead electrocardiogram, blood workup of adrenal, testicular, thyroid, and pituitary hormones as well as hematological, renal, and metabolic diseases (including T2DM and lipid abnormalities), urine drug screen, at-home actigraphy with sleep diary before the laboratory study for at least 1 week to demonstrate regular sleep patterns and no napping, and in-laboratory polysomnography to exclude sleep disorders, as described in detail previously (53). All participants provided written informed consent, and the study protocol was approved by the Institutional Review Board of the Lundquist Institute. Further supplementary details are available (54).

Study Design

Participants completed the laboratory study protocol twice, in randomized order, with either a dual cortisol and testosterone clamp or placebo control treatment (Fig. 1). For 1 to 2 weeks before each laboratory study session, participants were required to maintain their habitual dietary, activity, and sleeping schedule at home. Sleep periods were verified by at-home wrist actigraphy with sleep diary, and by time-stamped call-ins of bedtimes and wake times. For each laboratory study session, participants were admitted for an in-laboratory stay of 6 days, 5 nights duration. The first, baseline night of in-laboratory sleep opportunity was 10 hours (22:00–08:00). Participants were restricted to 4 hours of sleep (01:00–05:00) for the remaining 4 consecutive nights. Participants were continuously observed, and wakefulness was maintained by interactive conversation during scheduled wake periods. Sleep during scheduled sleep periods was monitored by means of polysomnography. Right before and after sleep restriction (days 1 and 5, respectively), blood was obtained fasting at 08:00 for the assessment of proinflammatory markers and gut and fat hormones. Immediately after, participants drank 75 g of glucose and began a 3-hour OGTT (08:30–11:30). Further supplementary details are available (54).

Diet

A nutrition history, food preference and allergy questionnaire, and a 24-hour food recall was obtained by a registered dietician during screening interviews to ensure that participants’ habitual diets were isocaloric and consisted of macronutrients within the recommended range (55). Participants were instructed to maintain their usual diet for at least 1 week prior to each in-laboratory stay. During the in-laboratory part of the study, standardized meals and snacks were provided, which were isocaloric (50-55% carbohydrate, 30-35% fat, 15% protein) and individualized using sex-specific equations based on sedentary activity levels for each participant (55) in order to ensure weight stability throughout the in-laboratory study sessions. Participants were required to consume all food provided, and outside food was not allowed. Identical meals were provided during each of the 2 laboratory study sessions.

Dual Hormone Clamp

800 mg ketoconazole was administered as a loading dose at 11:30, immediately after the baseline OGTT (day 1), and then beginning at 17:00, a 400 mg dose was administered every 6 hours through to the last day in the laboratory to suppress endogenous steroidogenesis (51, 56, 57). Ketoconazole was administered with a nondairy snack to maximize absorption. The first doses of transdermal testosterone and oral hydrocortisone were administered at 11:30 after the baseline OGTT, and subsequently at 08:00 daily while in the laboratory. Transdermal testosterone gel 75 mg (7.5 g of 10% gel), applied at 08:00, results in mean blood concentrations within the mid-physiological young adult range (50, 51). Oral hydrocortisone doses of 10 mg, 5 mg, and 2.5 mg, administered at 08:00, 14:00, and 20:00, respectively, model the diurnal pattern of cortisol at mid-physiological levels (52). In adult-onset hypopituitarism, insulin sensitivity has been shown to remain stable when cortisol is physiologically replaced in this fashion, as verified by hyperinsulinemic euglycemic clamp (58). Matching triple placebos (transdermal gel and capsules matching ketoconazole and hydrocortisone) were administered in the placebo treatment condition.

Oral Glucose Tolerance Test

For the 3-hour, intensively sampled OGTT, after oral administration of 75 g of glucose, blood samples were taken through an intravenous catheter every 5 minutes in the first hour, every 10 minutes in the second hour, and every 20 minutes in the third hour, for a total of 23 samples. Samples were centrifuged immediately, then frozen at −80 °C until assayed for C-peptide and glucose. Insulin sensitivity (Si), beta cell responsivity (total phi), and disposition index (the product of Si and total phi) were determined by minimal model analysis. This method has been extensively validated (59-63) and previously utilized by us (64, 65). Only Si values estimated from complete glucose and insulin profiles were utilized. The AUC for glucose, insulin and C-peptide was calculated using the trapezoid rule, and HOMA-IR and Matsuda index were determined as previously described (66, 67). Insulin clearance was calculated as the ratio of AUC of C-peptide over the AUC of insulin, which is commonly used as an index of hepatic insulin extraction given that the liver clears insulin but not C-peptide (68, 69).

Statistical Analyses

Measurements after sleep restriction were expressed relative to baseline, and then subjected to mixed-effects analysis of variance (ANOVA) with a fixed effect of treatment condition, order of conditions as a covariate, and a random effect over subjects on the intercept. Preplanned tests against zero of the measurements after sleep restriction, expressed relative to baseline, were embedded to assess the effect of sleep restriction in each of the 2 conditions separately. Overall insulin sensitivity was analyzed by means of mixed-effects multivariate analysis of variance (MANOVA) of the z scores (across the 2 conditions) of −HOMA-IR, Mi, and Si, expressed relative to baseline, with fixed effects of treatment condition and index and their interaction, and order of conditions as a covariate. Preplanned tests of the composite (ie, aggregate) z score differences against zero were embedded to assess the effect of sleep restriction in each of the 2 conditions separately. Since ketoconazole blocks the enzyme 11β-hydroxylase, and hence the conversion of 11-deoxycortisol to cortisol (70), we excluded 3 individuals who did not show an unequivocal increase in 11-deoxycortisol in a post hoc sensitivity analysis. The exclusion of these 3 individuals in these secondary analyses did not alter any of the primary intention-to-treat findings, which are presented below.

Results

Sleep Restriction Worsened Metabolic Parameters, Which Was Mitigated by Clamping Cortisol and Testosterone

Table 1 shows the baseline demographic data. Figure 2 shows the effects of sleep restriction and the dual clamp on overall insulin resistance, as quantified by composite z score, and on the 3 complementary measures from which it was derived: Mi, Si, and inverse HOMA-IR (ie, −HOMA-IR). As expected, sleep restriction in the placebo condition reduced overall insulin sensitivity (t180 = −5.50, P < 0.001). Consistent results were found for Mi (t64 = −5.05, P < 0.001) and Si (t50 = −3.37, P = 0.001), even after Bonferroni correction for multiple comparisons; and, albeit not significantly, for −HOMA-IR (t64 = 1.48, P = 0.144). There was a significant effect of treatment condition for overall insulin sensitivity (F1180 = 4.02, P = 0.046), which was also reflected in Mi specifically (F1,64 = 4.25, P = 0.043), indicating that the dual clamp altered the effect of sleep restriction. The dual clamp mitigated the effect of sleep restriction by more than 50%.

Table 1.

Baseline data

Subjects (N = 34)
Demographics
Age (yr) 33.26 (6.44)
Weight (kg) 79.16 (10.57)
BMI (kg/m2) 25.57 (2.57)
Summed testicular volume (mL) 47.80 (10.84)
Race (%)
 Asian 20%
 African American 20%
 Caucasian 55%
 Other 5%
Sleep at home
Sleep duration (h) 8.01 (1.41)
Polysomnogram
Sleep duration (h) 7.73 (0.89)
Sleep efficiency (%) 85.76 (7.66)
REM sleep (%) 20.41 (5.83)
Stage 1 sleep (%) 8.03 (2.84)
Stage 2 sleep (%) 62.33 (9.20)
Slow wave sleep (%) 9.25 (6.69)
Total arousal index (times/h) 3.67 (1.99)
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Data are shown as mean (SD) or % to nearest 5%.

Abbreviations: BMI, body mass index; REM, rapid eye movement.

Figure 2.

Figure 2.

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Effects of sleep restriction with placebo vs dual clamp treatment on overall insulin sensitivity (top left), and the component measures Mi (top right), Si (bottom left), and −HOMA-IR (bottom right). Error bars indicate standard error. Statistical significance of the (within-subject) effect of treatment on the difference between baseline and sleep restriction is indicated by large brackets, and treatment-specific differences between baseline and sleep restriction are indicated by the smaller brackets. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 3 shows the effects of sleep restriction on other parameters of glucose metabolism derived from the OGTT. In the placebo condition, sleep restriction caused both hyperinsulinemia and hyperglycemia, as shown by significant increases in insulin AUC (t65 = 5.64, P < 0.001) and glucose AUC (t65 = 5.25, P < 0.001), respectively. Furthermore, in the placebo condition there were significant decreases in total phi (t63 = −2.52, P = 0.014) and the disposition index (t50 = −2.66, P = 0.010), indicating that sleep restriction compromised pancreatic beta cell function and that the pancreatic response to insulin resistance was inadequate. The dual clamp muted the adverse effects of sleep restriction on hyperinsulinemia, as indicated by a significant effect of treatment condition for insulin AUC (F1,65 = 5.94, P = 0.018), but not hyperglycemia (glucose AUC), total phi, or disposition index. Figure 4 shows that the dual clamp did not mute the clearance of insulin or C-peptide AUC.

Figure 3.

Figure 3.

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Effects of sleep restriction with placebo vs dual clamp treatment on hyperinsulinemia (top left), hyperglycemia (top right), pancreatic beta cell function (bottom left), and pancreatic response to insulin resistance (bottom right). Error bars indicate standard error. Statistical significance of the (within-subject) effect of treatment on the difference between baseline and sleep restriction is indicated by large brackets, and treatment-specific differences between baseline and sleep restriction are indicated by the smaller brackets. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 4.

Figure 4.

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Effects of sleep restriction with placebo vs dual clamp treatment on insulin clearance (left) and C-peptide area under the curve (AUC) (right). Statistical significance of the (within-subject) effect of treatment on the difference between baseline and sleep restriction is indicated by large brackets, and treatment-specific differences between baseline and sleep restriction are indicated by the smaller brackets. *P < 0.05, **P < 0.01, ***P < 0.001.

The Induction of Insulin Resistance and the Dual Clamp Effect Were Not Explained by Changes in Proinflammatory Markers and Gut and Fat Hormones

Figure 5 (top) shows the effects of sleep restriction and the dual clamp on proinflammatory markers measured immediately before the OGTT. There was a trend toward an effect of treatment condition for IL-6 (F1,64 = 3.42, P = 0.069); IL-6 increased with sleep restriction in the dual clamp condition (t64 = 2.73, P = 0.008) and did not change in the placebo condition. TNFα decreased with sleep restriction in the placebo condition (t64 = −2.04, P = 0.045), but there was no change with sleep restriction in the dual clamp condition and there was no significant effect of treatment condition. Further, hs-CRP did not change with sleep restriction in either treatment condition, and there was no significant effect of treatment condition.

Figure 5.

Figure 5.

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Effects of sleep restriction with placebo vs dual clamp treatment on circulating concentrations of proinflammatory markers (top) and gut and fat hormones (bottom). Error bars indicate standard error. Statistical significance of the (within-subject) effect of treatment on the difference between baseline and sleep restriction is indicated by large brackets, and treatment-specific differences between baseline and sleep restriction are indicated by the smaller brackets. ‡P < 0.1, *P < 0.05. **P < 0.01, ***P < 0.001.

Figure 5 (bottom) shows the effects of sleep restriction and the dual clamp on gut and fat hormones measured immediately before the OGTT. There was a significant effect of treatment condition for PYY (F1,65 = 9.27, P = 0.003). Specifically, PYY did not change after sleep restriction in the placebo condition but decreased after sleep restriction in the dual clamp condition (t65 = −5.45, P < 0.001). Leptin increased with sleep restriction in the placebo condition (t65 = 2.60, P = 0.012), did not change significantly for the dual clamp condition, and there was no significant treatment effect. Ghrelin did not change after sleep restriction in either treatment condition, and there was no significant treatment effect.

Fig. 6 shows the effects of sleep restriction and the dual clamp on cortisol and testosterone measured immediately before the OGTT. Sleep restriction alone decreased cortisol (t65 = −2.7, P < 0.01), but did not alter testosterone. Cortisol increased (t65 = 3.6, P < 0.001) and testosterone decreased (t65 = −9.9, P < 0.001) under the dual clamp condition.

Figure 6.

Figure 6.

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Effects of sleep restriction with placebo vs dual clamp treatment on cortisol (left) and testosterone (right). Statistical significance of the (within-subject) effect of treatment on the difference between baseline and sleep restriction is indicated by large brackets, and treatment-specific differences between baseline and sleep restriction are indicated by the smaller brackets. *P < 0.05, **P < 0.01, ***P < 0.001.

Discussion

In this highly controlled laboratory study in young adult men, we demonstrated that fixing cortisol and testosterone by addback of cortisol and testosterone while blocking endogenous steroidogenesis by a dual hormonal clamp dampens the induction of insulin resistance due to sustained sleep restriction by more than 50%. Analogous results were found for hyperinsulinemia, but not for hyperglycemia. Thus, the impact of the dual clamp may be specific to insulin resistance and hyperinsulinemia. Alternatively, this apparent specificity may be a reflection of the stepwise progression in metabolic dysfunction associated with insulin resistance, which starts with hyperinsulinemia and progresses to hyperglycemia.

The standard replacement doses of cortisol (10, 5, and 2.5 mg orally) and testosterone (75 g/day transdermally) utilized in this proof-of-principle study are used in the clinic to mimic population mid-physiological exposure in castrate and glucocorticoid-deficient young men (50-52), but do not fully replicate the circadian and ultradian (ie, pulsatile) nature of endogenous cortisol and testosterone secretion. Although standard replacement starting doses were chosen, this dose of testosterone often requires uptitration, and ketoconazole inhibits cytochrome P450 3A4, which converts cortisol to 6β-hydroxycortisol, and may have prolonged the half-life of cortisol. These considerations may explain why a lower testosterone and higher cortisol were observed under the dual clamp condition. However, lower testosterone and higher cortisol should worsen, not improve, insulin resistance so our finding that clamping testosterone and cortisol mitigated the development of insulin resistance during sleep restriction is not diminished.

The development of insulin resistance with sleep restriction was substantially mitigated, but not fully prevented by the dual clamp, because we did not fully replicate endogenous exposure. In fact, we did not replicate the circadian and pulsatile rhythms of hormone secretion at all, and both impact molecular responses and physiological function in rodents and humans (71, 72). For example, a randomized controlled trial showed that hydrocortisone delivery that better replicated circadian rhythmicity further optimized weight, blood pressure, and glucose metabolism (73). Another randomized placebo-controlled crossover study showed that replicating both ultradian and circadian rhythmicity optimized working memory, reduced the perception of negative facial expressions and caused subtle differences in the neural processing of emotional input assessed by functional magnetic resonance imaging over and above that achieved by mimicking circadian rhythmicity alone (74). These studies reveal that relatively small changes in hormone concentrations that occur at critical time periods, such as during the late afternoon/early evening for cortisol signaling, are of considerable importance. Accordingly, investigating the effect of hormone replacement therapy that correctly mimics the temporal variation in circulating hormone levels on insulin resistance in hormone deficient individuals is required.

Even though inflammation is widely postulated to be a major factor in the development of insulin resistance (75-78), in the placebo condition we observed no significant changes in hs-CRP and IL-6 due to sleep restriction, which is consistent with a systematic meta-analysis of sleep restriction studies (10). Additionally, sleep restriction decreased TNFα, which would be expected to reduce, not increase, insulin resistance (79, 80). The dual clamp condition produced an increase in IL-6 after sleep restriction, but IL-6 is not associated with insulin resistance when infused to humans (80). As such, we found no evidence that proinflammatory mechanisms accounted for the insulin resistance effects in our study.

Similarly, in the placebo condition we saw no significant change in ghrelin and PYY with sleep restriction, which is consistent with a meta-analysis (81) and is partially consistent with some of the more recent literature (82, 83). Further, leptin levels were found to be increased after sleep restriction; however, this would be expected to improve, not worsen, insulin resistance (14). In the dual clamp condition, we observed a significant decrease in PYY after sleep restriction, which would be expected to worsen, not improve, insulin resistance (84, 85). As food intake during the study and the days preceding it was controlled as well, there was no evidence that the gut and fat hormones we measured could explain the insulin resistance effects in our study.

Limitations include the administration of hydrocortisone orally, not parenterally, but hydrocortisone taken orally without other intervention does not alter insulin resistance (58). Ketoconazole was coadministered to suppress endogenous steroidogenesis—an important aspect of our study design as endogenous steroidogenesis could otherwise have confounded our findings for the effects of the dual hormone clamp (51, 56, 57). Theoretically, ketoconazole could have direct effects on insulin resistance, but randomized controlled trials indicate that ketoconazole does not alter insulin sensitivity (86). Furthermore, our measurements of proinflammatory markers and gut and fat hormones were limited to one time of day in the morning, and this was an unpowered exploratory aim prone to both type 1 and type 2 errors. While measuring 24-hour profiles of these markers, as well as cortisol and testosterone, would have yielded additional insights but was not possible in this proof-of-concept study, our conclusion that clamping cortisol and testosterone mitigates the development of insulin resistance is not weakened and the possibility that blood sampling at night could have interfered with sleep in this proof-of-principle study was excluded by design. Future studies targeting late afternoon or early evening cortisol would be of particular interest. Finally, we measured total ghrelin, not the biologically active version of the hormone (acylated ghrelin), but the 2 are highly correlated so that one can be used as a surrogate for the other (87).

In conclusion, we mimicked a pattern of sleep restriction (4 nights of 4 hours/night sleep opportunity) that occurs in modern society and induces clinically meaningful metabolic changes. We measured the effects of sleep restriction in a highly controlled laboratory environment, and to assess metabolic outcomes we used an OGTT, which is more physiological as a glucose challenge than intravenous glucose (88). We showed that sustained sleep restriction causes metabolic harm through the development of insulin resistance, hyperinsulinemia, and hyperglycemia, as well as impairments in pancreatic beta cell functioning. Hyperinsulinemia is associated with obesity, and hyperglycemia leads to retinopathy and nephropathy. When accumulated over a lifetime, worsening insulin resistance, as well as these other metabolic changes, would be expected to lead to prediabetes and T2DM. Thus, repeated exposure to sleep restriction over the lifespan may explain in part the increased incidence of metabolic diseases with advancing age. Compliance with recommended sleep goals could help to prevent these long-term adverse health outcomes (5-7).

We also showed that fixing cortisol and testosterone exposure through a dual hormone clamp mitigates the development of insulin resistance from sleep restriction by more than 50%, thereby identifying a presumptive mechanism underlying the effect of sleep restriction on insulin resistance. Future studies should independently corroborate these findings in larger cohorts undergoing longer periods of sleep restriction and could separate the effects of clamping cortisol and testosterone to determine the relative contribution of each signaling pathway, since the current study manipulated both testosterone and cortisol simultaneously so that the relative contribution of either hormone could not be assessed. Nevertheless, our results demonstrate that in principle it might be plausible to develop methods, not necessarily that specifically manipulate testosterone or cortisol, to mitigate metabolic ill-health from sleep restriction without requiring more sleep. Development of such methods to augment sleep interventions—especially for those who occasionally or routinely cannot obtain adequate sleep due to work demands or medical conditions—may help to reduce the incidence of metabolic disorders such as T2DM.

Acknowledgments

We thank the participants, research coordinators and assistants, and the nursing and bionutritional staff of the Lundquist Institute Clinical and Translational Research Center at Harbor UCLA Medical Center, as well as Michelle Foster, Bjoern Brixius, Patrick O’Day, Michael Cherney, and the other technicians who performed assays.

Financial Support: This study is supported by the National Heart, Lung and Blood Institute (R01HL124211, and K24HL13632 to P.Y.L.), by the Kenneth T. and Eileen L. Norris Foundation (to P.Y.L.) and by the National Center for Advancing Translational Sciences through UCLA CTSI grant UL1TR001881. R.J.A. has received consulting fees from Janssen Pharmaceuticals, and contracted research and consulting fees from Strongbridge Biopharma.

Clinical Trial Information: ClinicalTrials.gov registration no. NCT02256865 (Hormonal Mechanisms of Sleep Restriction (https://clinicaltrials.gov/ct2/show/NCT02256865).

Author Contributions: P.Y.L. designed research; P.Y.L., K.P., W.Z., J.D.V., R.J.A., and A.I. performed research; D.L.S. and H.P.A.V.D. analyzed data; P.Y.L., D.L.S. and H.P.A.V.D. wrote the paper; all authors reviewed and edited the paper.

Glossary

Abbreviations

AUC

area under the curve

hs-CRP

high-sensitivity C-reactive protein

HOMA-IR

homeostatic model assessment for insulin resistance

IL-6

interleukin-6

Mi

Matsuda index

OGTT

oral glucose tolerance test

PYY

peptide YY (peptide tyrosine-tyrosine)

Si

insulin sensitivity

T2DM

type 2 diabetes mellitus

TNFα

tumor necrosis factor α

total phi

beta cell responsivity

Additional Information

Disclosures: None.

Data Availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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