The association of self-reported sleep and circadian measures with glycemic control and diabetes complications among young adults with type 2 diabetes.

We aim to examine the association of sleep duration, sleep quality, late chronotype, and circadian misalignment with glycemic control and risk of complications in young adults with youth-onset type 2 diabetes followed in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Self-reported sleep duration, quality, timing, and circadian misalignment were assessed via a modified Pittsburgh Sleep Quality Index (PSQI) questionnaire, and chronotype was assessed via the Morningness-Eveningness Questionnaire (MEQ). We examined diabetes complications including loss of glycemic control (defined as hemoglobin A1c ≥8%), hypertension, dyslipidemia, albuminuria, and diabetic peripheral neuropathy. Multivariable logistic regression models were constructed to assess associations between sleep and circadian measures with outcomes of interest, such as loss of glycemic control and diabetes complications. A total of 421 participants (34.2% male), mean age 23.6 ± 2.5 yr, mean body mass index (BMI) of 36.1 ± 8.3 kg/m2, and mean diabetes duration of 10.0 ± 1.5 yr were evaluated. Self-reported short sleep duration, daytime sleepiness, and sleep quality were not associated with loss of glycemic control or diabetes complications. Late self-reported bedtime (after midnight) on work/school nights, rather than self-expressed chronotype or circadian misalignment, was independently associated with loss of glycemic control. An association was seen between late bedtimes and albuminuria but was attenuated after adjusting for depression. In conclusion, late bedtime on work/school days, rather than short sleep duration, daytime sleepiness, or poor sleep quality, was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.NEW & NOTEWORTHY The prevalence of type 2 diabetes in youth is increasing at an alarming rate. Identifying potentially modifiable factors modulating glycemic control is critically important to reduce micro and macrovascular complications. In a large cohort of youth-onset type 2 diabetes, self-reported late bedtime on work/school days was independently associated with loss of glycemic control in this longitudinal cohort of young adults with youth-onset type 2 diabetes.

The moderating role of sleep duration on momentary relations between negative affect and loss-of-control eating in children and adolescents.

OBJECTIVE: Loss-of-control (LOC) eating is associated with eating disorders and obesity, and thus it is imperative to understand its momentary risk factors in order to improve intervention efforts. Negative affect has been proposed as a momentary risk factor for LOC eating, but the evidence for its effects in children and adolescents is mixed. Short sleep duration (which is very common in youth), may be one variable that moderates the relation between negative affect and subsequent LOC eating. As such, we aimed to examine the moderating role of within-person sleep duration on the momentary relations between negative affect and subsequent LOC eating. METHOD: We recruited children (N = 30) with overweight/obesity ages 8-14, who completed a 2-week ecological momentary assessment protocol assessing negative affect and LOC eating several times per day, while also wearing a sleep actigraphy device and completing sleep diaries. RESULTS: Consistent with hypotheses, within-person sleep duration moderated the next-day momentary relation between within-person negative affect and LOC eating, such that shorter sleep duration strengthened the positive relation between negative affect and loss-of-control eating. CONCLUSIONS: Results suggest that, in children and adolescents, fluctuations in sleep duration may influence susceptibility to losing control over eating after experiencing negative affect. Future research should further investigate other metrics of sleep disturbance as they relate to emotion regulation and LOC eating. Such research will set the stage for augmenting paediatric interventions to better target maintenance factors for LOC eating.

Naturalistic, multimethod exploratory study of sleep duration and quality as predictors of dysregulated eating in youth with overweight and obesity.

Although poor sleep has been found to adversely impact eating and weight regulation in youth, past research is limited by retrospective reporting and/or non-naturalistic designs. We investigated the feasibility of combining three momentary, ecologically valid approaches to assessing sleep and eating behavior, and associations between these constructs, among youth (aged 8-14y) with overweight/obesity (n = 40). Participants completed 14 overlapping days of actigraphy assessment and smartphone-based ecological momentary assessment (EMA) of eating behavior, of which 3 days also included computerized, self-guided 24-h dietary recall. Feasibility of completing measures concurrently was evaluated by generating frequencies of compliance. Associations between sleep indices and next-day eating behavior were examined via generalized estimating equations. Of 29 participants who provided EMA and 24-h recall data that aligned with previous night actigraphy data, both EMA and sleep data were available on an average of 8.6 out of 14 possible days, and both 24-h recall and sleep data on an average of 2.7 out of 3 possible days. Each additional hour of sleep was associated with consuming fewer calories from solid fats, alcohol, and added sugars (b = 0.70; p = .04). Combining naturalistic, momentary assessments of sleep and eating behavior appears to be acceptable in youth. Larger experimental studies are needed to further understand associations between sleep parameters and eating behavior.

Impact of obstructive sleep apnoea on insulin resistance in nonobese and obese children.

Obstructive sleep apnoea (OSA) has been inconsistently associated with insulin resistance and adverse metabolic states. We aimed to assess independent contributions of OSA to insulin resistance and dyslipidaemia in a large paediatric cohort.Habitually snoring children underwent overnight polysomnography, anthropometric measurements and fasting laboratory evaluations. Primary outcome measures included insulin, glucose, homeostasis model of insulin resistance, lipoproteins and sleep disturbance measures.Among 459 children aged 5-12 years, obesity was the primary driver of most associations between OSA and metabolic measures, but sleep duration was inversely associated with glucose levels, with N3 and rapid eye movement (REM) sleep being negatively associated and sleep fragmentation positively associated with insulin resistance measures. In children with mild OSA, the presence of obesity increased the odds for insulin resistance, while higher apnoea/hypopnoea index values emerged among obese children who were more insulin-resistant.The exclusive presence of interactions between OSA and obesity in the degree of insulin resistance is coupled with synergistic contributions by sleep fragmentation to insulin resistance in the context of obesity. Insufficient N3 or REM sleep may also contribute to higher glycaemia independently of obesity. Studies are needed to better delineate the roles of puberty and sleep fragmentation in insulin resistance and the metabolic syndrome.

Insulin-like growth factor-I and insulin-like growth factor binding protein-1 are related to cardiovascular disease biomarkers in obese adolescents.

CONTEXT: Insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-1 have been linked to cardiovascular disease (CVD) risk and pathophysiology in adults, but there are limited data in youth. OBJECTIVE: The aim of the study was to examine the relationship between IGF and IGFBP-1 with traditional and non-traditional CVD risk factors including inflammatory markers and body composition in an obese pediatric cohort. DESIGN: A cross-sectional study. SETTING: The study was carried out at a university children's hospital. SUBJECTS: Sixty-one obese non-diabetic adolescents. OUTCOMES: Fasting IGF-I, IGFBP-1, lipoprotein profiles, high-sensitivity C-reactive protein (hsCRP), and total adiponectin as well as insulin sensitivity measures, blood pressure (BP), and anthropometrics. RESULTS: IGFBP-1 was negatively associated with insulin sensitivity measures, body mass index (BMI), and diastolic BP in males. IGF-I was negatively associated with hsCRP (r = -0.479, p < 0.0005), and IGFBP-1 was positively associated with adiponectin (r = 0.545, p < 0.0005). The IGF-I/CRP and IGFBP-1/adiponectin associations remained significant when controlling for both BMI and insulin sensitivity index (SI ). Both IGF-I and IGFBP-1 were negatively associated with waist circumference (r = -0.327 and r = -0.275, respectively) and sagittal abdominal diameter (r = -0.333 and r = -0.371, respectively), while IGFBP-1 was negatively associated with fat mass (r = -0.347, p = 0.01) as well as neck circumference and fat-free mass in males. Controlling for BMI z-score and SI , IGFBP-1 remained negatively associated with diastolic blood pressure (r = 0.706, p = 0.001 and neck circumference (r = -0.548, p = 0.15) in males. CONCLUSIONS: IGF-I and IGFBP-1 associate with CVD risk markers and may add to clinical assessments of cardiometabolic dysfunction in youth.

Metabolic and glycemic sequelae of sleep disturbances in children and adults.

The prevalence of obesity in adults and children has increased greatly in the past three decades, as have metabolic sequelae, such as insulin resistance and type 2 diabetes mellitus (T2DM). Sleep disturbances are increasingly recognized as contributors to this widespread epidemic in adults, and data are emerging in children as well. The categories of sleep disturbances that contribute to obesity and its glycemic co-morbidities include the following: (1) alterations of sleep duration, chronic sleep restriction and excessive sleep; (2) alterations in sleep architecture; (3) sleep fragmentation; (4) circadian rhythm disorders and disruption (i.e., shift work); and (5) obstructive sleep apnea. This article reviews current evidence supporting the contributions that these sleep disorders play in the development of obesity, insulin resistance, and T2DM as well as possibly influences on glycemic control in type 1 diabetes, with a special focus on data in pediatric populations.

Anthropometric predictors of visceral adiposity in normal-weight and obese adolescents.

BACKGROUND: Obesity and fat distribution patterns [subcutaneous vs. visceral adipose tissue (VAT)] are important predictors of future cardiometabolic risk. As accurate VAT measurement entails imaging, surrogate anthropometric measurements that would be cheaper and quicker to obtain would be highly desirable. Sagittal abdominal diameter (SAD) may be better than other VAT surrogate measures in adults, but the value of SAD to predict magnetic resonance imaging (MRI)-determined VAT in adolescents of different races, sexes, and pubertal stages has not been determined. AIM: To test the hypothesis that SAD correlates more strongly with volumetric VAT than other anthropometric measurements, independent of age, sex, race, and Tanner stage. SUBJECTS AND METHODS: Twenty-eight normal-weight and 44 obese adolescents underwent Tanner staging, anthropometric examinations, and abdominal MRI for volumetric partitioned fat calculation. RESULTS: VAT increased exponentially in the body mass index (BMI) > 97th percentile range. SAD, waist circumference (WC), BMI, and BMI Z-score correlated strongly with VAT (correlation coefficients of 0.85-0.86, all p-values < 0.0005); waist-hip ratio was less predictive of VAT (r = 0.68, p < 0.0005). On hierarchical regression, the strongest predictors of VAT in obese subjects were BMI Z-score and SAD (R(2) = 0.34 vs. 0.31, respectively, p < 0.0005); in normal-weight subjects, most anthropometric measures predicted VAT equally (R(2) = 0.16-0.18, p-values = 0.018-0.026). CONCLUSIONS: Unlike adults, in obese adolescents, SAD is not the strongest predictor of visceral adiposity. BMI Z-score is equivalently predictive and, together with BMI, provides sufficient information to assess visceral adiposity; more specialized anthropometric measurements (e.g., SAD and WC) do not add additional predictive value.

Prediabetic obese adolescents have a more atherogenic lipoprotein profile compared with normoglycemic obese peers.

OBJECTIVE: To compare lipoprotein profiles of prediabetic to normoglycemic obese adolescents. STUDY DESIGN: Cross-sectional study of 95 obese, pubertal adolescents (12-17 years), who underwent oral glucose tolerance test, lipid panel, and lipoprotein subclass particle analysis (nuclear magnetic resonance spectroscopy). Univariate and linear regression analyses compared prediabetic and normoglycemic groups. RESULTS: Of 95 obese adolescents enrolled in the study, 22.1% (n = 21) had prediabetes. They were similar to normoglycemic adolescents (n = 74) in age, race, body mass index, standard lipids, total low-density lipoprotein particles (LDL-P), and total high-density lipoprotein particles (HDL-P). However, prediabetics had higher concentrations of small LDL-P (714.0 ± 288.0 vs 537.7 ± 266.5 nmol/L, P = .01) and smaller LDL-P size (20.73 ± 0.41 vs 21.18 ± 0.65 nm, P = .003), than normoglycemic youth. Prediabetics had higher small HDL-P (18.5 ± 3.8 vs 16.6 ± 3.9 umol/L, P = .046), lower large HDL-P (4.49 ± 2.0 vs 6.32 ± 2.6 umol/L, P = .004), and smaller HDL-P size (8.73 ± 0.31 vs 9.01 ± 0.39 nm, P = .003). After adjusting for demographics, Tanner stage, and body mass index using multiple linear regression, all differences remained significant except for small HDL-P. After additional adjustment for Homeostasis Model Assessment-Insulin Resistance Index, only LDL-P size difference remained significant. CONCLUSION: Obese prediabetic adolescents have a significantly more atherogenic lipoprotein profile compared with obese normoglycemic peers. Prediabetic adolescents may benefit from more aggressive interventions to decrease future cardiovascular risk.

Growth and development in type 1 diabetes.

PURPOSE OF REVIEW: The purpose of this review is to summarize the current literature on the subject of linear growth in children and adolescents with or at risk for type 1 diabetes mellitus (T1DM). RECENT FINDINGS: Poor glycemic control in T1DM is associated with growth hormone resistance, and improving glycemic control can improve linear growth. Newer reports suggest that the increasingly popular very low carbohydrate diets, may reduce linear growth velocity. SUMMARY: Linear growth during childhood is a complex process regulated influenced by genetic, hormonal, nutritional and environmental factors. Linear growth may be impaired in children with T1DM, correlating with poor metabolic control; an extreme example is Mauriac syndrome. This decrement in linear growth appears to be driven in part by a reduction in growth hormone responsiveness, leading to low insulin-like growth factor-1 (IGF-1) levels. Improving glycemic control can lead to improved IGF-1 levels and linear growth. Other factors associated with poor linear growth in T1DM include celiac disease and dietary alterations, with early reports suggesting that very low carbohydrate diets, if not carefully managed, may increase risk of attenuated linear growth. This review examines the latest data regarding the associations between T1DM and linear growth in children.

Childhood diabetes and sleep.

Sleep modulates glucose metabolism, both in healthy states and in disease. Alterations in sleep duration (insufficient and excessive) and obstructive sleep apnea may have reciprocal ties with obesity, insulin resistance and Type 2 diabetes, as demonstrated by emerging evidence in children and adolescents. Type 1 diabetes is also associated with sleep disturbances due to the influence of wide glycemic fluctuations upon sleep architecture, the need to treat nocturnal hypoglycemia, and the need for glucose monitoring and insulin delivery technologies. In this article, we provide an extensive and critical review on published pediatric literature regarding these topics, reviewing both epidemiologic and qualitative data, and provide an overview of the pathophysiology linking sleep with disorders of glucose homeostasis.

Longitudinal changes in vascular stiffness and heart rate variability among young adults with youth-onset type 2 diabetes: results from the follow-up observational treatment options for type 2 diabetes in adolescents and youth (TODAY) study.

AIMS: (1) To describe changes in arterial stiffness and heart rate variability (HRV) over a 5-year interval, (2) examine changes by sex and race-ethnicity, and (3) evaluate the risk factors associated with the longitudinal changes in arterial stiffness and HRV. METHODS: Participants with youth-onset type 2 diabetes enrolled in the observational follow-up phase of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial had arterial stiffness [(pulse wave velocity, augmentation index, brachial distensibility] and six indices of HRV measured 5 years apart. Multivariable linear regression models assessed risk factors associated with changes in the outcomes over time. RESULTS: At initial vascular assessment, the 304 participants were a mean age of 21 years, 34% male, and had a mean diabetes duration of 8 years. In more than half the cohort pulse wave velocity, augmentation index and HRV increased over 5 years (p<0.01). Brachial distensibility did not change. There were no differences in the 5-year change by race/ethnicity except for a single HRV measure, where non-Hispanic Blacks had greater worsening of parasympathetic function compared to non-Hispanic Whites, p = 0.008. Blood pressure was related to greater worsening in augmentation index and pulse wave velocity. Higher hemoglobin A1c over time was related to worsening pulse wave velocity and HRV. CONCLUSIONS: Arterial stiffness and HRV worsened over 5 years. Blood pressure and glycemic control may be potential targets to influence adverse changes in arterial stiffness and HRV in young adults with youth-onset type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00081328.

Visceral adiposity is related to insulin sensitivity and inflammation in adolescents with obesity and mild sleep disordered breathing.

OBJECTIVES: To evaluate the relationships between adipose tissue distribution, insulin secretion and sensitivity, sleep-disordered breathing, and inflammation in obese adolescents. METHODS: Cross-sectional study of 56 obese adolescents who underwent anthropometric measures, dual-energy X-ray absorptiometry, overnight polysomnography, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test. Correlation and regression analyses were used to assess relationships between adiposity, insulin secretion and sensitivity, measures of sleep-disordered breathing (oxyhemoglobin nadir, SpO2; apnea hypopnea index, AHI; arousal index, AI; maximum end-tidal CO2; non-REM sleep duration), and inflammation (high-sensitivity C-reactive protein, hsCRP). RESULTS: Subjects (55% female) were mean (SD) 14.4 (2.1) years, with BMI Z-score of 2.3 (0.4). AHI was >5 in 10 (18%) subjects and 1< AHI ≤5 in 22 (39%). Visceral adipose tissue area (VAT) was positively correlated with OGTT 1 and 2 h insulin and 1 h glucose, and hsCRP (r=0.3-0.5, p≤0.007 for each). VAT was negatively correlated with sensitivity to insulin (r=-0.4, p=0.005) and SpO2 nadir (r=-0.3, p=0.04) but not with other sleep measures. After adjustment for BMI-Z, sex, population ancestry, age, and sleep measures, VAT remained independently associated with insulin measures and 1 h glucose, but no other measures of glycemia. SAT was not associated with measures of glycemia or insulin resistance. CONCLUSIONS: Among adolescents with obesity, visceral adiposity was associated with insulin resistance, SpO2 nadir, and inflammation. The independent association of visceral adiposity with insulin resistance highlights the potential role of VAT in obesity-related chronic disease.

Management of Diabetic Ketoacidosis in Children and Adolescents with Type 1 Diabetes Mellitus.

Diabetic ketoacidosis (DKA) is the end result of insulin deficiency in type 1 diabetes mellitus (T1D). Loss of insulin production leads to profound catabolism with increased gluconeogenesis, glycogenolysis, lipolysis, and muscle proteolysis causing hyperglycemia and osmotic diuresis. High levels of counter-regulatory hormones lead to enhanced ketogenesis and the release of 'ketone bodies' into the circulation, which dissociate to release hydrogen ions and cause an overwhelming acidosis. Dehydration, hyperglycemia, and ketoacidosis are the hallmarks of this condition. Treatment is effective repletion of insulin, fluids and electrolytes. Newer approaches to early diagnosis, treatment, and prevention may diminish the risk of DKA and its childhood complications including cerebral edema. However, the potential for some technical and pharmacologic advances in the management of T1D to increase DKA events must be recognized.

The relationship between sleep-disordered breathing, blood pressure, and urinary cortisol and catecholamines in children.

STUDY OBJECTIVES: Hypertension is a complication of obstructive sleep apnea (OSA) syndrome in adults. A correlation between OSA syndrome and elevated blood pressure (BP) is suggested in children, but its pathogenesis remains unclear. Our aim was to study the effects of sleep and sleep apnea on BP and sympathetic nervous system activation as measured by serum cortisol and urinary catecholamines. We hypothesized that children with OSA syndrome would have higher BP, urinary catecholamines, and cortisol compared with controls. METHODS: We measured BP during polysomnography in 78 children with suspected sleep-disordered breathing and 18 nonsnoring controls. BP was measured during wakefulness and every 30-60 minutes throughout the night. All participants had 24-hour urinary catecholamine and free cortisol collections 48 hours before polysomnography. RESULTS: BP varied with sleep stage; it was highest during wakefulness and N1 and lowest during non-rapid eye movement stage 3. Children classified as high apnea-hypopnea index (AHI) snorers (AHI >5 events/h) had a greater prevalence of systolic hypertension (57%) than low-AHI snorers (22%) and nonsnoring controls (22%; P = .04). The high-AHI snorers also had higher diastolic BP (P < .02) as well as blunted nocturnal diastolic BP changes during sleep (P = .02) compared with low-AHI snorers (AHI <5 events/h). Twenty-hour urinary free cortisol and 24-hour urinary catecholamines were not associated with BP. CONCLUSIONS: BP in children varies with sleep stage. OSA is associated with systolic hypertension, higher BP during rapid eye movement sleep, as well as elevation of diastolic BP and blunted BP changes with sleep.

Association of sleep disturbances with obesity, insulin resistance and the metabolic syndrome.

Insufficient sleep, which has become endemic in recent years, has been variably associated with increased risk of obesity, disorders of glucose and insulin homeostasis, and the metabolic syndrome; to a lesser degree, so has excessive sleep. This review summarizes recent epidemiological and pathophysiological evidence linking sleep disturbances (primarily abnormalities of sleep duration) with obesity, insulin resistance, type 2 diabetes and the metabolic syndrome in children and adults.

Gender dimorphism in pediatric OSA: Is it for real?

In epidemiologic studies focused on adults, obstructive sleep apnea (OSA) has higher prevalence in men than in women. The evidence supporting a gender-related discrepant prevalence of OSA is however much more tenuous in children. Here, we aimed to review the evidence concerning gender- based differences in the prevalence of OSA in children, and if so, to examine the evidence with the intent to identify potential factors that may account for this putative association. Gender-based perception and reporting of clinical manifestations of OSA may be modulated by several social and cultural factors in children. Among those factors, gender may crucially affect the reporting of symptoms such as snoring, and therefore markedly skew the male:female prevalence ratios of OSA. On the other hand, hormonal changes associated with puberty, may be playing a role, albeit a relatively smaller one than previously construed. Gender bias in OSA is most likely due to complex interactions between several physiological and epidemiologic factors that are clearly operational in adults. However, the evidence of clear gender-based differences in OSA prevalence or severity remains unclear in pre-pubertal children, and may be detectable in adolescents only when concurrent obesity is also present. Furthermore, no published evidence emerged supporting increased susceptibility to OSA-related in pre-pubertal boys vs. girls, except in obese adolescents or in girls with elevated testosterone levels. Future research in OSA may give clues on the role of gender-related hormonal changes as a modulating factor in childhood.

Angiopoietin-2 and soluble Tie-2 receptor plasma levels in children with obstructive sleep apnea and obesity.

OBJECTIVE: Obstructive sleep apnea (OSA) is a prevalent condition, especially in children with obesity, and is associated with increased risk for metabolic syndrome (MetS). Angiopoietins have been identified as potential biomarkers of endothelial dysfunction and MetS. In adults, angiopoietin-2 (Ang-2) and its soluble receptor (sTie-2) are associated with diabetes, hypertension, and obesity and could be increased in children with OSA and obesity, particularly those with evidence of cardiometabolic alterations. METHODS: One hundred twenty-six children (7.4 ± 2.0 years) were consecutively recruited and underwent overnight polysomnography, as well as endothelial function and BMI z score assessments and a fasting blood draw the morning after the sleep study. In addition to lipid profile, glucose and insulin levels, and homeostatic model assessment of insulin resistance (HOMA-IR), Ang-2 and sTie-2 concentrations were determined. RESULTS: Children with obesity and OSA had significantly elevated plasma Ang-2 and sTie-2 levels compared to corresponding controls with and without obesity. Furthermore, endothelial function (Tmax) and HOMA-IR were linearly and independently associated with Ang-2 and sTie-2 levels. In a small subset of children (n = 14), treatment of OSA by adenotonsillectomy resulted in reductions of Ang-2 and sTie-2 (P < 0.01). CONCLUSIONS: Ang-2 and sTie-2 plasma levels are increased in pediatric OSA and obesity, particularly when endothelial dysfunction or insulin resistance is detectable, and appear to decrease upon OSA treatment.