Leptin, insulin and thyroid hormones in a cohort of Egyptian obese Down syndrome children: a comparative study

The aim of the work

The current study was designed to clarify differences in some obesity- related hormones in a group of prepubertal Down syndrome children.

Statistical analysis

Data were analyzed using SPSS statistical package version 16. Categorical variable (sex) was presented as number and percent. Chi square test was used for comparison between groups. Numerical variables were tested for normality by Kolmogorov-Smirnov test and found to be non parametric in distribution. So Kruskal Wallis was used for comparison between four groups while, Mann Whitney was used for comparison between two groups. Spearman's correlation coefficient was used to test the correlation between variables within each group of patients. P≤0.05 was considered to be statistically significant.

IR in children with DS

One of the characteristics of the person with trisomy 21 is the propensity for becoming obese[2]. IR is the most common metabolic alteration related to obesity[20]. Considering the upper limit of FBG up to 5.55 mmol/L[21], normal fasting range for insulin varies from 5 to 15 μIU/ml[22] and fasting insulin greater than 15μIU/ml indicated IR[12]. This study showed significant higher median values of FBG, insulin and IR (assisted by HOMA-IR) in Down (OD, NOD) versus non Down (OND, NOND) groups with highest median values in OD group. This could be attributed to high levels of adipose tissue (which is more central than peripheral) in such children[22, 23] and the fact that central adiposity is more associated with IR[22]. Magge et al.[24] observed significantly higher percent body fat, non significantly higher insulin and glucose in children with DS than unaffected siblings, while no significant difference in HOMA-IR. It was suggested previously in small size study, (15 cases, including one prepubertal child with DS) that increased HOMA-IR and high rate of glucose production indicated presence of peripheral and hepatic IR in adolescent with DS[22].

Considering one of the two definitions of IR syndrome in children:[1] the presence of any three or more of hyperinsulinemia, overweight, high systolic blood pressure, high triglycerides, low HDL-C and impaired fasting glucose; and[2] the presence of hyperinsulinemia and at least two of the other five risk factors[25]. Our study reported an association between hyperinsulinemia, impaired fasting glucose and obesity in obese Down children, that could make them at higher risk to develop severe metabolic complications. In contrary Flore et al., 2008[26] could not display IR in a group of young non obese adults with DS.

Leptin, leptin-R & obesity in DS children

Considering leptin and leptin-R, a higher median value of leptin in OD children was observed in this study, however, no significant difference in leptin and leptin -R were observed between OD versus OND, indicating an increase in median leptin values, a marker of leptin resistance in obese children irrespective to the cause of obesity. This was in contrary to the suggestion of presence of genetic basis for obesity (three copies of chromosome 21) that might be a cause of more severe leptin resistance in DS[24]. Previously Considine et al.[10] concluded that obese individuals have higher leptin levels than normal weight individuals, and obesity is associated with leptin resistance. This belief is in harmony with our results that showed positive correlation between leptin and leptin-R in obese groups (OD, OND).

Insulin leptin interrelationship

Consistent with insulin/leptin arcuate nucleus of the hypothalamus axis, insulin and glucose appear to stimulate leptin secretion in adipocytes. In response, leptin decreases insulin secretion via direct action on leptin receptors in pancreatic B-cells while enhancing their actions and consequently improves whole body insulin sensitivity[27].

So, obesity promoted - hyperinsulinemia stimulates leptin release. Like other biological signaling pathways, leptin appears to regulate its own receptor signaling or increased central leptin results in reduced hypothalamic leptin receptor expression and leptin signaling. Hence, obesity promotes hyperleptinemia, which in turn self promotes leptin resistance and further obesity, making leptin resistance both a consequence and cause of obesity[27].

Thyroid dysfunction in DS

Thyroid dysfunction is highly prevalent in DS persons. The clinical symptoms and signs of both DS and hypothyroidism are overlapping to some extent e.g. hypotonia, mental retardation, growth failure, macroglosia, obesity etc.[28]. The presence of undetected hypothyroidism in children with DS could compound the problems in already compromised situation.

We observed significantly higher FT₄ but not exceeding reference range (1–5 years: 11.9 – 22.1; 6–10 years: 11.5-19.96pmol/L)[29] with no significant difference in TSH values in Down versus non Down groups. This was in contrary to previous data reported by Konings et al.[4] and Shaw et al.[28] who found higher mean TSH values (6.5±1.3, 5.4±2.9mU/l respectively) in face of normal FT₄ or T₄. They hypothesized that thyroid gland in children with DS needs an elevated TSH pressure to produce sufficient hormones[4]. However, we observed elevated serum TSH values with normal thyroxine levels in four cases, three in OD and one in NOD groups denoting subclinical hypothyroidism, associated with CK above 90U/l[30].

Hypotonia, CK & associated myopathy in DS children

Considering hypotonia as a risk factor for obesity in DS, we suggest that it could be associated with muscle breakdown. CK is considered the primary marker for muscle breakdown, in response to exercise, a portion of the population has exaggerated increases in CK[31, 32]. Reasons for an exaggerated response are not fully understood but may reflect genetics[31], fiber type, an underlying myopathy, and/or some other environmental behavioral factors, including fitness level[33]. Furthermore variations in muscle mass have been proposed to account for interracial differences in total CK activity[34]. Our results showed significantly higher median CK value in OD compared with OND group. Also a positive correlation was found between CK and TSH in OD group. Associated myopathy either endocrine[35] (hypothyroid related myopathy) or infectious secondary to viral infection[36], strenuous physical activity[32] may be the underlying causes for these mildly elevated CK values and muscle weakness could be added to the hypotonia which is a part of genetic predisposition of the disease.

Limitations

The study was small in size, single center, cross sectional comparative study. It relied solely on BMI for age percentiles of Center of Disease Control and Prevention as an indicator of body fatness because it is simple, easily obtained than skin folds thickness, presence of standardized BMI curves and cut-off points defining overweight & adiposity in childhood[37] and correlates well with DEXA[38]. Previous results, suggest that skin fold measurements may only slightly improve (8%) the estimation of body fatness among children who are obese (BMI ≥95th CDC percentile)[39]. Furthermore it may help determine if an overweight child may have excess body fatness[39] and this group of children were not included in our study. Finally due to racial variation and poor inter- and intra- observer reliability skin fold thickness equations should be validated in each population and it is difficult to standardize[39]. While for waist circumference, no internationally accepted cut points for either the classification of obesity or presence of increased metabolic risk in children as in adult[25], furthermore, no data on population with DS can be found on this regard[40]. Body fat itself is not necessarily a precise measure of health risk. As stated by the recent AMA expert committee[41], “High levels of body fat are associated with increasing health risks. However, no single body fat value, whether measured as fat mass or as percentage of body weight, clearly distinguishes health from disease or risk of disease”.