Waking up to sleep extension for cardiometabolic health

Type 2 diabetes mellitus (T2DM) is an increasingly prevalent disease associated with macrovascular complications (ischemic heart disease, stroke, and peripheral arterial disease) and microvascular complications (retinopathy leading to blindness, nephropathy progressing to end-stage kidney disease, and neuropathy associated with chronic pain and amputations). Hyperglycemia in T2DM results from a combination of insulin resistance and the inability of pancreatic beta cells to secrete sufficient insulin to overcome insulin resistance. The severity and progression of T2DM complications are related to the degree and duration of hyperglycemia, hypertension, and dyslipidemia. T2DM used to occur mainly in older individuals, but driven by the rise in obesity, is increasingly seen at a younger age (early-onset T2DM), particularly during adolescence (youth-onset diabetes), where prolonged exposure to T2DM cardiometabolic derangements and a more accelerated disease progression translates to a significant impact on morbidity and mortality [1]. For every decade of earlier onset of T2DM, there is an associated lower life expectancy of 3–4 years [2].

Preventing early-onset T2DM is an urgent priority. A commonly overlooked factor contributing to T2DM is insufficient sleep, with a substantial supporting body of evidence from cross-sectional and prospective population studies. The relationship between insufficient sleep and metabolic dysfunction is bidirectional. In human laboratory studies, sleep restriction has been associated with a negative impact on whole body, peripheral, and liver insulin sensitivity and there has been a suggestion that sleep restriction results in accelerated metabolic aging [3]. Adolescents are at high risk for insufficient sleep and downstream metabolic derangement because of physiological delayed sleep phase exacerbated by prevalent behaviors such as technology use near bedtime and social pressures for early wake times.

A missing evidence gap in the relationship between insufficient sleep and metabolic dysfunction is examining the role of sleep extension through randomized controlled trials. Dutil et al. aimed to address this gap through the sleep manipulation in adolescents at risk of type 2 diabetes (SMART2D) randomized controlled trial from Canada. Short sleeping (≥6.5 to <9 hour sleep/night) adolescents with obesity but without T2DM or sleep disorders (N = 36; 53% female; 56% White; aged 15.1 ± 1.3 years; 99.9th body mass index percentile) were recruited and completed the study. The majority of participants had a family history of chronic disease, over half reported an average to low quality of life and the average daily screen time was over 3 hours. The majority (97.2%) did not meet the guideline-recommended daily physical activity. Sleep difficulty was reported by 77.8%. The demographic, behavioral, and clinical data placed the participants at risk for T2DM. After a week of habitual sleep, participants were randomized to sleep extension through increasing time in bed (by 1.5 h/night) or a similar duration reduction in time in bed for seven nights under free-living conditions with sleep measured through wrist-worn actigraphy. This was then followed by a week of habitual sleep as a washout followed by completing the increased or decreased time intervention in bed based on previous allocation. Participants were advised to avoid daytime napping. Cardiovascular and metabolic measures (including from a 75 g oral glucose tolerance test) were collected after a 12-hour overnight fast subsequent to each intervention. There was a mean habitual total nightly sleep time of 7 hours 31 min/night and total nightly sleep time increased on average by 1 hour 02 minutes with increased time in bed and decreased by 1 hour 19 minutes with reduced time in bed. The Matsuda index, a measure of whole-body insulin sensitivity that is highly correlated with body glucose disposal during the euglycemic insulin clamp, increased by about 20% with sleep extension compared to habitual or decreased sleep. Improvement in insulin sensitivity was also noted using other measures including homeostatic model assessment (HOMA) measures, quantitative insulin sensitivity check index (QUICKI), and single-point insulin sensitivity estimator (a predictor of future dysglycaemia in children with excess adiposity) [4].

Conducting randomized clinical trials of sleep interventions are challenging but made more complicated by the COVID-19 pandemic for the SMART2D study. Like the SMART2D study, the majority of clinical trials of sleep extension are of short duration and may not translate to tangible long-term outcomes. Similarly, most studies are single-center and may not be generalizable. In adolescents, pubertal development and its associated hormonal alterations (including insulin counter-regulatory hormones such as growth hormone and cortisol) affect metabolic responses. Counter-regulatory hormone changes with sleep intervention were not studied. Reduction in sympathetic nervous system activity with sleep extension has been proposed as a mechanism for improvements in glycemic control, but this was also not examined in the SMART2D study. Unlike other studies, the SMART2D study did not observe any changes in energy or macronutrient intake. Food diaries tend to be inaccurate and a 3-day food diary used in the SMART2D study may not have sufficiently captured any changes in food intake. Previous studies have reported a reduction in energy intake during sleep extension in adolescents and adults. A randomized sleep extension study of 80 adults overweight with habitual sleep duration of < 6.5 hours reported that sleep extension reduced daily energy intake by 270 kcal per day compared to the control group without sleep extension [5]. Sleep extension may reduce intake of energy-dense and high glycemic-load foods, particularly in the evening, which may translate to improvements in glycemic control. In the SMART2D study, physical activity during wakefulness was marginally increased (6.8%) with sleep extension compared to habitual sleep but was not significant compared to sleep reduction. Alterations in energy expenditure with sleep deprivation or extension have been inconclusive.

The pathophysiological aberrations of T2DM extend beyond dysglycaemia. In the SMART2D study, there were improvements in lipids with sleep extension. However, there were few participants with hypertension, a key driver of macrovascular disease in T2DM, and no significant changes in blood pressure were reported with sleep extension. A recent randomized study of 18 mainly white adults with habitual sleep of < 6.5 hours investigated the impact of sleep extension by increasing time in bed for 6 weeks [6]. The increase in total sleep time, the primary study outcome, achieved with the sleep extension intervention was about 72 minutes. There were significant reductions in secondary outcome measures including HOMA insulin resistance, and systolic and diastolic blood pressure.

Results of emerging randomized clinical trials of sleep extension across adolescents and adults are promising and further confirm a role of sleep in cardiometabolic health [6–8]. The available randomized clinical trials demonstrate that it is possible to extend sleep using simple sleep hygiene measures at least for a short period. It is now time to study the impact of sleep extension on cardiometabolic health over longer periods and examine the impact of extending sleep in short sleepers at risk of cardiometabolic disease on body weight, food intake, energy expenditure, measures of glycemic control, and measures of cardiovascular disease such as blood pressure and lipids. Focusing sleep extension interventions on individuals with short habitual sleep may demonstrate a greater beneficial cardiometabolic effect. These studies should also provide mechanistic insights into the impact of sleep on cardiometabolic health including changes in autonomic nervous system activity, the hormonal milieu, the gut microbiome, and potential epigenetic alterations. Future lifestyle intervention studies should also consider a multi-modal approach that adds sleep extension to the management of food intake and physical activity considering the complex interactions amongst all these factors. In the meantime, adding improvements in sleep to public health interventions for obesity and T2DM prevention at an early age should be strongly considered [3].

Funding

There is no funding associated with this work.

Disclosure Statement

Financial disclosures: None. Nonfinancial disclosures: None.