Adiponectin has attracted tremendous scientific interest as a candidate biomarker of MetS in childhood obesity [9, 10, 20, 21], and as a therapeutic target for obesity [22], owing to pediatric studies reported that after weight reduction, adiponectin increases with associated improvement in insulin sensitivity [23, 24].
It has been hypothesized that DS could be a "metabolic disease", in which trisomy of HSA21 has a key role in altered energy metabolism that is strongly related to dysregulation of insulin and insulin signaling pathways [25]. Moreover, all the body adiposity indicators such as BMI, WC, waist to height ratio, %BF, and FM were reported to be significantly higher in obese-DS children and adolescents compared to age-and sex-matched normal-weight controls [26–28].
In the current study, obese-DS children exhibited significantly excess body adiposity with profound central fat distribution as indicated by higher WC, trunk-FM, and trunk/appendicular FM ratio in obese-DS compared to age-and BMI Z-score-matched obese-controls which point to the higher risk for MetS in obese-DS.
Practically, the frequency of MetS was significantly higher in the obese-DS (56%) compared to obese-control (34%). Central adiposity was the most prevalent alteration in MetS components in both obesity-groups, that was significantly higher in obese-DS compared to obese-control (78% vs. 56%), while the frequencies of the remaining altered MetS components were also higher in obese-DS compared to obese-control, but did not reach significant levels. Interestingly, fasting serum insulin and HOMA-IR values as well as the frequencies of insulin resistance indices including hyperinsulinemia (fasting insulin ≥ 15 µU/ml) and HOMA-IR (> 2.5) were significantly higher in obese-DS compared to obese-control.
Considerable progress has been made in the clarification of the central role of insulin resistance as a key-element linking obesity and CMRFs clustering, and the potential mechanisms leading to insulin resistance development in obese children [29]. Previuos studies in obese adolescents have indicated that insulin resistance is related to a particular centeral fat distribution and ectopic fat accumulation [30, 31]. In this context, obese-DS with MetS were significantly younger in age and exhibited pronounced central fat distribution and higher fasting serum insulin and HOMA-IR values than obese-control with MetS.
Data regarding the circulating adiponectin level in DS children are scarce [26, 32, 33]. Tenneti et al. [32] reported a lower adiponectin levels in normal weight children with DS. Similar findings were detected by Gutierrez-Hervas et al. [26] in adolescents with DS with variable degree of adiposity. Corsi et al. [33] found that adiponectin levels were significantly higher in three different age cohorts of normal-weight DS individuals including children (n = 23; age 2–14 years), adults (n = 14; age 20–50 years) and elders (n = 13; age > 60 years) compared to healthy controls. Moreover, they reported age-related increments in adiponectin levels among DS individuals, where elders with DS had significantly higher adiponectin levels compared to the younger and middle age counterparts.
Interestingly, individuals with DS represent a still unsolved biological/clinical paradox. Although an increment of classical biochemical risk factors for atherosclerosis should induce an elevated risk of atherosclerosis in normal-weight DS individuals, DS has been considered an atheroma-free model [33], with evident low risk of atherosclerosis-related morbidity and mortality in healthy subjects with DS during adulthood and senility [34]. Reasons of this discrepancy remain obscure. Corsi et al. [33] suggested that elevated adiponectin level in healthy adults and elders with DS may play a protective role against atherosclerosis by regulating endothelial activation.
This study showed for the first time that serum adiponectin level was significantly lower in prepubertal obese-DS compared to obese-controls, despite being matched for age-and BMI Z-score. We also detected a decreasing trend in adiponectin concentrations with increasing the severity of obesity in both obesity groups that was more pronounced in obese-DS than in obese-control. Interestingly, obese-DS with MetS also exhibited significantly lower median adiponectin value than obese-control with MetS.
The observed high degree of discordance between obese-DS and matched obese-control in respect to body adiposity indicators, the frequency of MetS and its components, serum adiponectin and insulin resistance indices point to intrinsic idiosyncratic factors other than traditional risk factors may contribute to the increased risk for cardiometabolic disorders in subjects with DS that are closely related to trisomy of HSA21.
As to the association between serum adiponectin level and CMRFs, serum adiponectin was inversely correlated with age, BMI, WC, total-FM, trunk-FM, FBG, fasting serum insulin, HOMA-IR, and triglycerides and was positively correlated with HDL-C in obese-DS. These associations might related to the effect of adiponectin on metabolic homeostasis whereas adiponectin enhances fatty acids and triglycerides catabolism, promotes glucose uptake by skeletal muscle and increasing serum HDL-C level by its action on hepatic lipase activity [7, 8].
Interestingly, central obesity was the predominant CMRFs for MetS and strongly correlated with low adiponectin levels, thus evident needs to motivate individuals with DS to participate and adherence to regular and consistent exercise programs to reduce abdominal obesity as prophylactic and as a treatment for MetS.
Previous studies conducted on non-DS children and adolescents with obesity reported variable and non-consistent associations between adiponectin level and various CMRFs [35–38]. It has been presumed that the variation in genetic backgrounds in different ethnicity are major factors in determining the level of adiponectin expression and its association with various CMRFs [39, 40].
For clinical practice, we explored the validity of serum adiponectin level for the diagnosis of MetS in obese-groups, the results of ROC curve analysis showed that adiponectin seems to perform better in the diagnosis of MetS in obese-DS (AUC = 0.808) than in obese-control (AUC = 674), with lower cut-off value in obese-DS compared to obese-control (4.8 µg/ml vs. 5.5 µg/ml, respectively). Our results were comparable to the reports from studies conducted on non-DS obese children and adolescents of different ethnicity. The optimal cut-off values of serum adiponectin for diagnosis of MetS among Japanease children was 6.65 µg/ml (AUC = 0.672) [41], while among Chinese children was 4.5 ug/ml for boys (AUC = 0.697) and was 5.2 ug/ml for girls (AUC = 0.689) [42], and among Italian children was 10.9 mg/dl (AUC = 0.72) [43].
The principal limitation of the current study is the cross-sectional design, which precludes us to identify the causal direction between adiponectin concentrations and CMRFs in DS children. However, as strength, our study is the first to explore body adiposity, MetS components, insulin resistance indices, and serum adiponectin level among prepubertal obese-DS children in comparison to age-and BMI-matched obese-controls. Our results collectively suggest that low adiponectin level seems to be an important mediator in the development of MetS in DS children as have been suggested in individuals without DS [44].