High sensitivity of melatonin suppression response to evening light in preschool-aged children.

Light at night in adults suppresses melatonin in a nonlinear intensity-dependent manner. In children, bright light of a single intensity before bedtime has a robust melatonin suppressing effect. To our knowledge, whether evening light of different intensities is related to melatonin suppression in young children is unknown. Healthy, good-sleeping children (n = 36; 3.0-4.9 years; 39% male) maintained a stable sleep schedule for 7 days followed by a 29.5-h in-home dim-light circadian assessment (~1.5 lux). On the final night of the protocol, children received a 1-h light exposure (randomized to one of 15 light levels, ranging 5-5000 lux, with ≥2 participants assigned to each light level) in the hour before habitual bedtime. Salivary melatonin was measured to calculate the magnitude of melatonin suppression during light exposure compared with baseline levels from the previous evening, as well as the degree of melatonin recovery 50 min after the end of light exposure. Melatonin levels were suppressed between 69.4% and 98.7% (M = 85.4 ± 7.2%) during light exposure across the full range of intensities examined. Overall, we did not observe a light intensity-dependent melatonin suppression response; however, children exposed to the lowest quartile of light intensities (5-40 lux) had an average melatonin suppression (77.5 ± 7.0%) which was significantly lower than that observed at each of the three higher quartiles of light intensities (86.4 ± 5.6%, 89.2 ± 6.3%, and 87.1 ± 5.0%, respectively). We further found that melatonin levels remained below 50% baseline for at least 50 min after the end of light exposure for the majority (62%) of participants, and recovery was not influenced by light intensity. These findings indicate that preschool-aged children are highly sensitive to light exposure in the hour before bedtime and suggest the lighting environment may play a crucial role in the development and the maintenance of behavioral sleep problems through impacts on the circadian timing system.

Good agreement between hyperinsulinemic-euglycemic clamp and 2 hours oral minimal model assessed insulin sensitivity in adolescents.

BACKGROUND/OBJECTIVE: Rates of dysglycemia are increasing in youth, secondary to obesity and decreased insulin sensitivity (IS) in puberty. The oral minimal model (OMM) has been developed in order to measure IS using an easy oral glucose load, such as an oral glucose tolerance test (OGTT), instead of an hyperinsulinemic-euglycemic clamp (HE-clamp), a more invasive and time-consuming procedure. However, this model, following a standard 2 hour- OGTT has never been validated in youth, a population known for a different physiologic response to OGTT than adults. Thus, we compared IS measurements obtained from OMM following a 2-hour OGTT to HE-clamp and isotope tracer-assessed tissue IS in adolescents. We also compared the liver/muscle-specific IS from HE-clamp with other liver/muscle-specific IS surrogates following an OGTT previously validated in adults. METHODS: Secondary analysis of a cross-sectional study. Adolescent girls with (n = 26) and without (n = 7) polycystic ovary syndrome (PCOS) (14.6 ± 1.7 years; BMI percentile 23.3%-98.2%) underwent a 2-hour 75 g OGTT and a 4-phase HE-clamp. OMM IS (Si), dynamic Si (Sid ) and other OGTT-derived muscle and liver IS indices were correlated with HE-clamp tissue-specific IS. RESULTS: OMM Si and Sid correlated with HE-clamp-measured peripheral IS (r = 0.64, P <.0001 and r = 0.73; P <.0001, respectively) and the correlation coefficient trended higher than the Matsuda index (r = 0.59; P =.003). The other tissue-specific indices were poorly correlated with their HE-clamp measurements. CONCLUSION: In adolescent girls, the 2-hour OMM provided the best estimate of peripheral IS. Additional surrogates for hepatic IS are needed for youth.

Too Late and Not Enough: School Year Sleep Duration, Timing, and Circadian Misalignment Are Associated with Reduced Insulin Sensitivity in Adolescents with Overweight/Obesity.

OBJECTIVES: To examine the relationship between insulin resistance (IR) and sleep/circadian health in overweight/obese adolescents. We hypothesized that insufficient and delayed sleep would be associated with IR in this population. STUDY DESIGN: Thirty-one adolescents (mean age, 16.0 ± 1.4 years; 77% female) with body mass index ≥90th percentile for age/sex were recruited from outpatient clinics at a children's hospital. Participants underwent 1 week of objective home sleep monitoring with wrist actigraphy during the academic year. A 3-hour oral glucose tolerance test was conducted, followed by in-laboratory salivary dim-light melatonin sampling every 30-60 minutes from 5 p.m. to noon the next day. Regression analyses between sleep and circadian variables with IR were examined. RESULTS: Longer sleep time and time in bed on weekends and weekdays and earlier weekday bedtime were significantly associated with better insulin sensitivity. Participants who obtained less than the median duration of sleep per night (6.6 hours) had evidence of IR with compensatory insulin secretion compared with those obtaining ≥6.6 hours of sleep. A wider phase angle between bedtime and melatonin onset, indicating a later circadian timing of sleep onset, was significantly associated with IR. CONCLUSIONS: Short sleep duration, later weekday bedtime, and later circadian timing of sleep were associated with IR in a cohort of adolescents with overweight/obesity during the school year. Further research is needed to better understand the physiology underlying these observations and to evaluate the impact of improved sleep and circadian health on metabolic health in this at-risk population.

Estimating Insulin Sensitivity and Beta-Cell Function from the Oral Glucose Tolerance Test: Validation of a new Insulin Sensitivity and Secretion (ISS) Model.

Efficient and accurate methods to estimate insulin sensitivity (SI) and beta-cell function (BCF) are of great importance for studying the pathogenesis and treatment effectiveness of type 2 diabetes. Many methods exist, ranging in input data and technical requirements. Oral glucose tolerance tests (OGTTs) are preferred because they are simpler and more physiological. However, current analytical methods for OGTT-derived SI and BCF also range in complexity; the oral minimal models require mathematical expertise for deconvolution and fitting differential equations, and simple algebraic models (e.g., Matsuda index, insulinogenic index) may produce unphysiological values. We developed a new ISS (Insulin Secretion and Sensitivity) model for clinical research that provides precise and accurate estimates of SI and BCF from a standard OGTT, focusing on effectiveness, ease of implementation, and pragmatism. The model was developed by fitting a pair of differential equations to glucose and insulin without need of deconvolution or C-peptide data. The model is derived from a published model for longitudinal simulation of T2D progression that represents glucose-insulin homeostasis, including post-challenge suppression of hepatic glucose production and first- and second-phase insulin secretion. The ISS model was evaluated in three diverse cohorts including individuals at high risk of prediabetes (adult women with a wide range of BMI and adolescents with obesity). The new model had strong correlation with gold-standard estimates from intravenous glucose tolerance tests and hyperinsulinemic-euglycemic clamp. The ISS model has broad clinical applicability among diverse populations because it balances performance, fidelity, and complexity to provide a reliable phenotype of T2D risk.

Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions.

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.