الفهرس 
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Abstract
Overweight and obesity, which represent one of the most global public health problems of the 21st century, have dramatically increased among children and adolescents. They are regarded as major causes of morbidity and mortality, and hence this issue necessitates the discovery of novel biomarkers for both obesity and its associated metabolic disorders.
Reviewing literature, no studies was found to assess the relation between Zonulin and Copeptin as potential markers for obesity and their related disorders in both children and adolescents. However, the current study aimed to compare the serum Zonulin and Copeptin levels between obese and non-obese children, assess the relation between plasma Zonulin and Copeptin with each other and with the metabolic and anthropometric factors and to assess the role of plasma Zonulin and Copeptin in obese children as possible markers of metabolic disturbances.
This cross sectional case-control study was carried out in the ”Management of Visceral Obesity and Growth Disturbances” clinic at the ”Medical Research Center of Excellence (MERC)”, of the National Research Centre. This study included 111 children: 45 males (with mean age 8.74 ± 1.60 years) and 66 females (with mean age 8.78 ± 1.73 years). Participant children were classified, according to their BMI percentile, into two groups: group (1) which included 72 obese children (with BMI >95th percentile, and mean age 9.20 ± 1.55 years) and group (2) which included 39 healthy control children (with BMI range 15th - 85th percentile and mean age 7.97 ± 1.59 years). All participants were also classified according to insulin resistance into 2 groups: insulin-resistant group and non-insulinresistant group according to HOMA-IR cut off point (> 3.16).
Full history was taken from all participant children. They were also undergone general clinical examination, measurement of blood pressure, anthropometric parame-ters(including weight, height, and neck, waist, hip and mid upper arm circumferences, ACHTR, and skin folds thick-ness). BMI, waist hip ratio, and waist height ratio were calculated.Peripheral and central obesity indices and body composition were also assessed.Levels of fasting blood sugar, insulin, HOMA-IR, lipid profile, Zonulin and Co-peptin were assessed for all participant children.
Ethical approval number was 17/ 123; obtained from the Ethics Committee of the National Research Centre.
There were insignificant sex differences in all the studied variables: age, clinical, anthropometric parameters and laboratory investigations; among total sample, obese and control children. So the analysis was completed as one sample; without sex differentiation.
The obese children had significant higher values than control ones regarding all the studied clinical and anthropometric parameters, and most of the studied laboratory investigations: FBS, Insulin, HOMA-IR, Chol, and Copeptin, and significant lower value of Zonuline and HDL. There were insignificant differences between obese and control children regarding LDL and TG.
The insulin- resistant group had significant higher values in FBG, insulin levels and HOMA-IR, and significant lower values of BMR than non-insulin resistant group. There were insignificant differences between the two groups regarding all the studied clinical, anthropometric parameters, the other body composition variables (TBW, FM, FFM and BF %) and laboratory investigations: lipid profile, Zonulin and Copeptin.
Zonulin had significantly lower values and Copeptin had significantly higher values among obese children than control ones, and insignificant differences between insulin- resistant group and non- insulin- resistant group. There was highly significant negative correlation between them in all groups, even after exclusion of the effect of age.
Among total sample serum Zonulin had significant negative correlations and Copeptin had significant positive correlations with age, DBP, most the studied anthropometric measurements (WT, HT, BMI, NC, WC, HC, WHTR, and MUAC); except WHR and ACHTR; all skin fold thickness (BSF, TSF, SCSF, SISF and ABSF), peripheral and central obesity indices and body composition (TBW, FFM and FM); except Fat% and BMR. Among the obese group, these adverse correlations persisted regarding Wt, BMI, WC, HC, WHTR, SCSF and body composition in addition to BMR. While among the control group, these adverse correlations persisted regarding Wt, Ht. HC and MUAC only. Serum Copeptin had significant negative correlations with WHR, all studied skinfold thickness (BSF, TSF, SCSF, SISF, ABSF) and peripheral obesity index.
Partial Correlations; to exclude effect of age; among total sample, obese and control children revealed that the correlations between serum Zonulin on one side, and all the studied anthropometric measurements, skin fold thickness and body composition disappeared, and significant negative correlation with central obesity index appeared among obese children. While serum Copeptin still had significantly positive correlations with BMI, MUAC, ACHTR, SCSF, ABSF, central obesity index, FM and BMR among obese children, and with NC, WC, MUAC, ACHTR, all skinfold thickness, Peripheral and central obesity indices among control children.
Among insulin resistant (obese) group, serum Zonulin had significant negative correlations and Copeptin had significant positive correlations with BMI, NC, HC and WHTR. Moreover, serum Copeptin significantly positive correlated with WC, TBW, FFM and FM. Among non-insulin resistant (non-obese) group, serum Zonulin had significant negative correlations and Copeptin had significant positive correlations with age, Wt, Ht, BMI, NC, WC, HC, WHTR, MUAC, ACHTR, all skinfold thickness; except BSF; peripheral and central obesity indices, TBW, FFM and FM. In addition, serum Zonulin had significant negative correlations with BSF. While serum Copeptin had significantly positive correlated with DBP. Partial Correlations; to exclude effect of age, among insulin resistant group and non-insulin resistant group, revealed that the correlations between serum Zonulin and Copeptin on one side, and all the studied anthropometric measurements, skin fold thickness and body composition disappeared. So, the age had an effect on the correlations between Zonulin and Copeptin on one side and all the anthropometric measurements under study and the body composition in the different groups, particularly on the Zonulin.
Among total sample Copeptin significantly negative correlated with insulin, while among control group, it significantly positive correlated with TG. Among control children, serum Zonulin significantly negative correlated with TG and positively correlated with HDL. Among non-insulin resistant group, serum Zonulin had significant positive correlations with HDL.
Partial Correlations; to exclude effect of age; among total sample and obese children revealed that Serum Zonulin significantly correlated positively and Copeptin significantly correlated negatively with Insulin and HOMA-IR. While among control children, serum Copeptin only significantly negative correlated with Insulin and HOMA-IR. On the other side, among insulin resistant and non- insulin resistant groups; serum Copeptin only had significant positive correlation with fasting blood glucose in both groups (p<0.05).
Limitation of the study
Number of cases as well as controls included in the study was small to allow generalization of the conclusion of the study.
Conclusions
• Zonulin had significantly lower values and Copeptin had significantly higher values among obese children than control ones, and insignificant differences between insulin- resistant group and non- insulin- resistant group. There was highly significant negative correlation between them in all groups, even after exclusion of the effect of age.
• Serum Copeptin had better association with childhood obesity markers more than Zonulin; however neither of them could be used as potential biomarkers for meta-bolic disturbance; as no one of them had significant as-sociatiom with any variables of lipid profile among obese children.
• Both serum Zonulin and Copeptin can be used as po-tential biomarker for insulin-resistance in children; con-sidering the age effect; as serum Zonulin significantly positive correlated and Copeptin significantly negative correlated with Insulin and HOMA-IR among obese children.
• The age has an effect on the relation between either Zonulin or Copeptin and the obesity markers (all the anthropometric measurements under study and the body composition) in the different groups, particularly on the Zonulin.
Recommendations
Both serum Zonulin and Copeptin can be used as predictors for insulin-resistance in children.
In obese children, Zonulin did not correlate with any of the metabolic parameters, except with serum HDL-C levels among normal weight and non-Ir groups. However, further studies identifying the Zonulin receptor and/or other possible cofactors will be required to elucidate the exact role of zonulin in obesity and/or IR.
However, the limitation of the used human zonulin ELISA kit, which measures not only zonulin but also other proteins in the same family, such as haptoglobin; must be taken into consideration. Therefore, in future studies, it will be necessary to use other markers of intestinal permeability, together with zonulin, to strengthen this relationship.
Additional studies with a larger sample size at different age groups are necessary to further clarify the role of Zonulin and Copeptin and relation between them in obesity and obesity related disorders.