Article published by the Endocrine Society Article published by the Endocrine Society

Elevated retinol-binding protein 4 (RBP4) levels may contribute to the development of metabolic abnormalities, but prospective studies evaluating the association between childhood RBP4 levels and metabolic syndrome (MS) in adulthood are lacking. We investigated whether RBP4 levels during childhood predict cardiometabolic risk at 10-year follow-up. The relationships between RBP4 levels, the established adipokines (leptin and adiponectin) and the components of MS were examined in 3445 school-aged children recruited in 2004 for the Beijing Child and Adolescent Metabolic Syndrome study. In 2015, 352 of these individuals completed an in-depth follow-up examination. Participants with higher childhood RBP4 levels had adverse cardiometabolic profiles at follow-up. Those with incident or persistent MS had higher baseline RBP4 levels than those who never exhibited the elements of MS. Moreover, baseline RBP4 predicted hyperglycemia (OR per SD increase = 1.48, P = 0.009), elevated triglyceride (OR = 1.54, P < 0.001), elevated blood pressures (OR = 1.46, P = 0.015), MS (OR = 1.68, P = 0.002) and insulin resistance (OR = 1.44, P = 0.015) in the 10-year follow-up phase, independent of baseline BMI. Significant improvements were seen for the net reclassification improvement and integrated discrimination index after adding childhood RBP4 levels into the risk models using conventional cardiometabolic risk factors in predicting MS at follow-up (P < 0.05). Leptin and adiponectin demonstrated the expected associations with metabolic disorders. Childhood RBP4 serves as a risk factor for subsequent development of MS and its components, independent of pediatric obesity. Incorporating childhood RBP4 into conventional cardiometabolic risk assessment models significantly improves the prediction of MS.

Background/objectives Short sleep is an obesity risk factor, however, little is known about its interplay with genetic predisposition and pathways involved in obesity pathogenesis, especially in the longitudinal setting. We aimed to investigate a possible sleep-gene interaction for childhood obesity risk, and whether the interaction in childhood longitudinally contributes to obesity risk at a 10-year follow-up and further to test if there is any mediation through the leptin pathway. Subjects/methods A total of 3211 children from China (6–18 years) at baseline and 848 participants at 10-year follow-up from the Beijing Child and Adolescent Metabolic Syndrome (BCAMS) cohort study were analyzed. Baseline leptin concentrations and 12 established adult body mass index (BMI) loci were examined for the associations with habitual sleep duration. Results After adjusting for covariates, including pubertal stages and behavioral factors, short sleep duration at baseline was significantly associated with increased overweight/obesity risk at both baseline and follow-up. Genetic predisposition scores (GPS), particularly consisting of leptin-related SNPs (GPS_leptin), were robustly associated with baseline overweight/obesity in children who slept ≤8 h/day (P < 0.001), whereas the association was ablated in those who slept ≥10 h/day (P > 0.05). Comparable observations were made at follow-up. Mediation analysis revealed a modest direct effect of the GPS_leptin-sleep interaction on BMI at baseline, while a significant indirect effect of this interaction was found to be mediated principally through elevated leptin (proportion: 52.6%); moreover, the mediation effect via leptin remained stable over 10 years. Conclusions This study suggests that shorter sleep duration in children from China (< 8h/day), compared to longer sleep duration (≥10 h/day), has a long-term impact on the association of polygenic risk for obesity from childhood to young adulthood and leptin pathway explains a key mechanism via a modification effect. Therefore, adequate sleep duration during childhood is important for the early prevention of obesity, especially if there is a genetic predisposition to this trait.

Betatrophin has been recently reported to play a role in glucose homeostasis by inducing beta-cell proliferation in mice. However, studies in human are inconsistent. As a nutritionally-regulated liver-enriched factor, we hypothesize that betatrophin might be regulated by vitamin D, and ignorance of vitamin D status may explain the discrepancy in previous human studies. The aims of this study were to assess the association between circulating betatrophin and glucose homeostasis as well as other cardiometabolic variables in a cohort of youths at risk for metabolic syndrome and test the possible influence of vitamin D status on the association. 559 subjects aged 14–28 years were recruited from Beijing children and adolescents metabolic syndrome study. All underwent a 2 h-oral glucose tolerance test. Serum levels of betatrophin, 25-hydroxy-vitamin D as well as adipokines including adiponectin and fibroblast growth factor 21 (FGF21) were measured by immunoassays. The relationships between betatrophin and insulin resistance, beta-cell function, other cardiometabolic variables and vitamin D status were evaluated. Participants in the highest quartile of betatrophin levels had the highest levels of total cholesterol (P < 0.001), triglyceride (P < 0.001) and low-density lipoprotein cholesterol (P < 0.001) and the lowest levels of vitamin D (P = 0.003). After stratification by vitamin D status, betatrophin in subjects with vitamin D deficiency were positively correlated with unfavorable metabolic profiles including high blood pressures, dyslipidemia and hyperglycemia, whereas betatrophin in those with higher vitamin D levels only showed negative association with fasting insulin, 2 h-insulin, and insulin resistance. In addition, adiponectin and FGF21 demonstrated the expected associations with metabolic parameters. Elevated betatrophin levels were associated with cardiometabolic risk factors in this young population, but the association was largely dependent on vitamin D status. These findings may provide valuable insights in the regulation of betatrophin and help explain the observed discrepancies in literature.

Objective We aimed to assess haemoglobin A1c (HbA1c) for the diagnosis of pre-diabetes and diabetes in a population of Chinese youths at risk of metabolic syndrome. Setting Beijing, China. Participants A total of 581 subjects aged 14–28 years underwent evaluation including an oral glucose tolerance test (OGTT). Insulin sensitivity, β-cell function and a number of cardiovascular disease risk factors were evaluated. Receiver operating characteristic (ROC) curves were used to assess the screening efficacy of HbA1c. Results Using OGTT data as a standard, the majority (70.0%, 7/10) of subjects with diabetes would have been diagnosed with HbA1c ≥6.5%. In contrast, only 28.1% (16/57) of subjects with pre-diabetes possessed elevated HbA1cs, while the majority (68.4%) had normal HbA1cs. On the contrary, a total of 8.1% (39/479) of youths in the normal HbA1c category (<5.7%) and 21.3% in the pre-diabetes category had pre-diabetes. In the ROC analysis, the area under the curve (AUC) for HbA1c identifying pre-diabetes was 0.680(95% CI 0.640 to 0.719); the optimal threshold was 5.5%, with a sensitivity of 61.4% and specificity of 68.5%. For type 2 diabetes mellitus, the AUC for HbA1c was 0.970 (0.952 to 0.982), and the optimal threshold was 6.1%, with a sensitivity of 90.0% and a specificity of 98.7%. Applying these new cut-offs, pre-diabetic participants (HbA1c 5.5%–6.1%) had lower disposition index and higher risk of dyslipidaemia (OR=1.61,95% CI 1.10 to 2.37) and metabolic syndrome (OR=2.09, 1.27 to 3.45) than those with normal HbA1c (<5.5%). Conclusion The American Diabetes Association’s established HbA1c criteria for pre-diabetes and diabetes (5.7% and 6.5%) may not be appropriately applied to adolescents and young adults in China. Our findings suggest that those with HbA1c of 5.5%–6.1% already exhibit impaired β-cell function and increased cardiometabolic risk factors which may warrant intervention. Trial registration number NCT03421444.