Conclusions
In this study, we identified a significant association of impaired rest-activity circadian rhythm, indexed by decreased RA (the robustness) and increased IV (fragmentation of the rhythm), with increased 2-hour postchallenge plasma glucose concentrations and IGT in a general population of adults without diabetes. Although we cannot determine the directionality of the associations in this cross-sectional study, the finding of impaired rest-activity circadian rhythm already existing in participants with IGT, a pre-diabetic state, suggests that circadian dysfunction may contribute to early disease pathogenesis. While it has been shown in previous studies that late acrophase was associated with type 2 diabetes, we did not observe the effect of timing (L5 start time or M10 start time) on glucose tolerance.
The strength and regularity of daily rest-activity rhythm assessed by accelerometer have been linked with diabetes and diabetic complications in both cross-sectional and prospective studies.15 16 33 However, the study on the associations of rest-activity rhythms with metabolic regulation is an emerging area, especially in glucose metabolism. The majority of previous studies34–38 have used accelerometer data to explore the relationships of physical activity or sleep parameters with glucose control, rather than a chronobiological analysis of rest-activity rhythm. To the best of our knowledge, there are only two recent studies, one in older men and the other in young adults, that examined the association between rest-activity rhythm parameters and glucose concentration and both studies only included fasting blood sample measurements. The study by Xiao et al16 in men aged ≥65 years did not observe an association between rest-activity rhythm and fasting glucose, but did observe that lower amplitude and reduced overall rhythmicity were associated with higher fasting insulin and HOMA-IR, indices of insulin resistance, indicating that beta cell compensation can still keep a stable blood glucose level in the presence of insulin resistance in the fasting status. Consistent with their findings in older participants, we also observed that lower amplitude or higher fragmentation was associated with elevated fasting insulin and HOMA-IR in a broader age range of adults. However, the significance disappeared after further adjustment of BMI and history of hypertension (ie, model 3). Impaired rest-activity rhythm has been associated with higher BMI39 and higher BMI is a significant contributor to insulin resistance. There is a possibility that BMI can be a mediator rather than a confounding factor for the relationship between rest-activity rhythm and insulin resistance. Therefore, BMI was not used as a covariate in the study by Xiao et al.16 We repeated model 3 (online supplemental table 2) by excluding BMI from the list of the covariates and did observe that the significant associations of lower amplitude with elevated fasting insulin and HOMA-IR remained. Future prospective or interventional studies are warranted to distinguish between potential mediator or confounding effects of BMI in the relationship between rest-activity rhythm and glycemic metabolism. The study by Hoopes et al33 was conducted in 52 healthy adults aged 18–25 years and did not observe an association between rest-activity rhythm and fasting glucose. The negative finding from this study might be due to the small sample size and the relatively healthy status of the participants. An increase in postprandial glucose concentration may occur when fasting glucose levels are still ‘in the normal range’. It has been well acknowledged that increased 2-hour glucose during an oral glucose test is a better predictor of all-cause mortality and morbidity than fasting glucose levels.40 41 Our consistent findings of the association between increased 2-hour glucose levels and impaired rest-activity rhythm in all three models indicate that mildly disrupted circadian rhythm induced by our daily activities might be linked with impaired glucose homeostasis when our body reacts to a glucose challenge (ie, after a meal).
How the molecular machinery of circadian clock is trained by synchronizers such as food/feeding (ie, a glucose challenge) to coordinate energy metabolism inside the body is still under study. Prior studies showed that phosphorylation by nutrient-responsive adenosine monophosphate-activated protein kinase destabilizes cryptochrome 1, one of the core components that constitute the negative feedback loop of circadian rhythm, and links nutrient signals to circadian clocks.42 In addition, the circadian positive feedback loop may also be affected by the intracellular redox state. NADH (the reduced form of nicotinamide adenine dinucleotide) and NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate), the redox cofactors of nicotinamide adenine dinucleotide, increase the binding of Clock:BMAL1 and NPAS2:BMAL1 to DNA, while the oxidized forms, NAD(P)+, inhibit this process.43
Our study has several limitations that should be considered in interpreting the results. First, the NHANES-based cross-sectional study design limits the ability to understand the causal inferences between blunted rest-activity rhythm and IGT. Second, the participants involved in this analysis were examined in the morning session after a 9-hour fast. Endogenous circadian variations in fasting glucose levels and 2-hour postchallenge glucose levels have been observed with poorer glucose control occurring at evening or midnight.44 Therefore, performing the glucose tolerance test at multiple time points of the day should be included in future studies to provide more solid evidence on the link between daily rest-activity-induced mild circadian disruption and glucose control disturbance. Third, the OGTT in the NHANES study did not include measurements of other metabolic characteristics, such as glucose disposal and uptake or 2-hour insulin levels, so it provides limited information regarding the change in insulin sensitivity during the OGTT process.
In summary, the finding that abnormalities of rest-activity rhythm exist in adults with IGT may indicate that glucose metabolism has already been impaired by mild disruptions in the circadian rhythm. Future studies focusing on intervention programs to promote normalization of circadian rhythms through modifications of lifestyle and behavioral factors should be conducted to confirm whether the relationship between blunted rest-activity rhythm and IGT is causal.