Ambulatory blood pressure monitoring in obese children: role of insulin resistance.

OBJECTIVES: To investigate the relationship between ambulatory blood pressure (ABPM) parameters and insulin resistance in obese children. METHODS: A population of 56 obese prepubertal children was recruited for the study. They underwent ABPM, an oral glucose tolerance test and complete physical examination, including adiposity indexes such as body mass index (BMI), skinfolds, waist-to-hip ratio (WHR) and fat mass. RESULTS: The standard deviation score for BMI was significantly correlated with 24-h systolic blood pressure (SBP) (r = 0.30; P = 0.02) and diastolic blood pressure (DBP) (r = 0.29; P = 0.03), daytime SBP and DBP (r = 0.28; P = 0.04 and r = 0.32; P = 0.02), night-time SBP and DBP (r = 0.32; P = 0.01 and r = 0.27; P = 0.04). Fat mass was correlated with 24-h SBP (r = 0.46; P = 0.005), daytime SBP (r = 0.40; P = 0.01) and night-time SBP (r = 0.49; P = 0.03). No correlations were found between ABPM parameters and WHR. Furthermore, significant correlations were found between insulin resistance indexes, such as the homeostasis model assessment of insulin resistance and quantitative insulin-sensitivity check index, and 24-h DBP (r = 0.34; P = 0.01 and r = -0.29; P = 0.03), daytime DBP (r = 0.35; P = 0.009 and r = -0.34; P = 0.01) and daytime SBP (r = 0.32; P = 0.02 and r = -0.27; P = 0.04). Only 24-h and daytime DBP remained correlated with insulin resistance after adjustment for obesity. The analysis of the circadian rhythm of blood pressure revealed that 24 out the 56 children were non-dippers. CONCLUSIONS: The results of the present study indicate that adiposity and insulin resistance have an important role in influencing blood pressure in obese children, and also show a high prevalence of non-dipping phenomenon. This is of particular relevance because blood pressure tracks from childhood into adulthood and an already early-life high blood pressure is associated with an increased cardiovascular risk.

Long-term follow-up of children treated for acute lymphoblastic leukemia and the recovery of beta-cell function.

We studied the evolution of beta-cell function in 32 children treated for acute lymphoblastic leukemia (ALL) through a long-term follow-up after completion of therapy. Our results show that although alterations of the glucose metabolism persists after stop-therapy they are reversible with time.

Increased oxidative stress in prepubertal severely obese children: effect of a dietary restriction-weight loss program.

Oxidant-antioxidant status was investigated in a group of severely obese prepubertal children in comparison with healthy subjects and in relation to a dietary restriction-weight loss program. All subjects underwent anthropometric measurements and determination of lipid profile, lag phase, malondialdehyde (MDA), and vitamin E. Compared with controls, obese children had a significantly higher body mass index (BMI) (28.97 +/- 2.42 vs. 16.03 +/- 1.88 kg/m2; P = 0.0002) and waist-to-hip ratio (WHR) (0.89 +/- 0.03 vs. 0.80 +/- 0.01; P = 0.0004); lag phase and vitamin E levels were significantly decreased [24.05 +/- 16.21 vs. 43.16 +/- 10 min (P = 0.004) and 21.12 +/- 14.96 vs. 35.54 +/- 13.62 micromol/liter (P = 0.02), respectively], whereas MDA was significantly increased (0.90 +/- 0.31 vs. 0.45 +/- 0.24 nmol/mg; P = 0.001). Both lag phase and MDA significantly correlated with BMI [respectively, r = -0.34 (P = 0.004) and r = 0.57 (P = 0.002)] and WHR [respectively, r = -0.63 (P = 0.0001) and r = 0.38 (P = 0.04)]. Oxidant status normalized after 6 months of dietary restriction [lag phase, 59.11 +/- 14.74 min (P = 0.002); MDA, 0.47 +/- 0.09 nmol/mg (P = 0.003)], which was associated with a reduction of BMI (27.34 +/- 1.87 kg/m2; P = 0.003), WHR (0.87 +/- 0.02; P = 0.001), and fat mass (34.49 +/- 2.68%; P = 0.008), but returned to baseline levels together with fatness indexes after another 6 months of free diet. Altered oxidant-antioxidant status is already present in prepubertal severely obese children and is reversible with a dietary restriction-weight loss program, which should be highly encouraged and maintained over time in this age group.

Persistence of impaired pancreatic beta-cell function in children treated for acute lymphoblastic leukaemia.

Treatment for acute lymphoblastic leukaemia can induce alterations of glucose metabolism, but long-term follow-up data on this topic are still absent. We aimed to study glucose metabolism by intravenous and oral glucose tolerance testing in 32 children affected by acute lymphoblastic leukaemia and who were off-therapy for at least 1 year. 22 (69%) children presented with impaired first-phase insulin response, which in nine children was associated with impaired glucose tolerance and in one child with overt diabetes. Fasting insulin (4.65 mU/L, 95% CI 1.1-8.1; p=0.008), insulinogenic index (0.46; 0.02-0.98; p=0.03), and homoeostatic model assessment beta-cell function (80.1, 7.2-153; p=0.02) were reduced in the children with impaired insulin response. Chemotherapy for acute lymphoblastic leukaemia is associated with beta-cell function damage, which persists even after therapy has been stopped.

Association between rs12970134 Near MC4R and adiposity indexes in a homogenous population of Caucasian schoolchildren.

BACKGROUND: To assess whether previously identified obesity-susceptibility loci were associated with overweight/obesity risk in a homogeneous population of Caucasian schoolchildren and whether these associations varied with age. METHODS: Seven hundred and forty-five schoolchildren (353 boys, mean age: 8.3 ± 1.4 years) underwent anthropometric assessments. A saliva sample was collected for DNA extraction and assessment of 19 single-nucleotide polymorphisms previously associated with obesity. RESULTS: Only the rs12970134 in the MC4R gene was significantly associated with overweight/obesity risk, with a higher frequency of the AA risk genotype in children with a BMI >85th (8.3%) than in those with a BMI <85th percentile (3.0%), p = 0.001; odds ratio (95% CI) of 1.544 (1.192-1.998), p = 0.001, after adjusting for age, sex and pubertal stage. BMI standard deviation scores (SDS) and waist-to-height ratio (W/Hr) progressively increased across the rs12970134 genotypes (GG vs. AG vs. AA): BMI SDS, p = 0.004; W/Hr, p = 0.009. When dividing the study population into two groups based on the median age of participants (8.3 years), the differences in BMI SDS and W/Hr across the MC4R genotypes persisted only in children older than 8.3 years. CONCLUSIONS: In a population of Caucasian schoolchildren, the rs12970134 MC4R variant was significantly associated with excess body weight, particularly in children older than 8 years of age.

GNRH analog therapy in girls with early puberty is associated with the achievement of predicted final height but also with increased risk of polycystic ovary syndrome.

OBJECTIVE: GNRH analog (GNRHa) therapy has not been supported by beneficial effects on adult stature in girls with early puberty. Furthermore, an increased prevalence of polycystic ovary syndrome (PCOS) has been described in girls treated for central precocious puberty. Women with PCOS are at increased risk of cardiometabolic dysfunctions and infertility. Our aim was to assess GNRHa effectiveness on reaching adult stature and the risk of PCOS in girls with early puberty. DESIGN: Longitudinal study of GNRHa-treated and GNRHa-untreated girls at baseline and at final height. METHODS: Twenty-five GNRHa-treated girls and 55 controls were compared. Insulin resistance (IR; homeostasis model assessment of IR (HOMA-IR) and glucose-to-insulin ratio (G/I)), the effect of GNRHa on final height, and the prevalence of PCOS were assessed. RESULTS: In GNRHa-treated girls, no significant difference was found between predicted final height and final height, whereas a significant difference was detected in untreated girls (P=0.0001). At final height, GNRHa-treated girls showed higher HOMA-IR and lower G/I (P=0.03 for both) as well as higher DHEAS and androstenedione levels (P=0.02 and P=0.01 respectively) than untreated girls. The prevalence of PCOS and hyperandrogenemia was significantly higher in GNRHa-treated adolescents than in untreated adolescents (36 and 14.5% respectively, P=0.04; 56 and 23.6% respectively, P=0.01). Finally, gonadotropin-suppressive therapy was significantly related to PCOS during adolescence (P=0.03). CONCLUSIONS: In girls with early puberty, GNRHa therapy is associated with the achievement of predicted final height; nevertheless, this treatment seems to act as an independent risk factor for the development of PCOS already during adolescence.

The possible role of liver steatosis in defining metabolic syndrome in prepubertal children.

Insulin resistance is a key component of the metabolic syndrome (MS) and is strongly associated with liver steatosis. Our aim was to evaluate whether MS should be diagnosed already in obese prepubertal children and whether its prevalence is influenced by the inclusion of hepatic steatosis as a diagnostic criterion. Eighty-nine obese children (43 boys; age median [range], 8.5 [6-10] years) were enrolled. Metabolic syndrome was diagnosed according to a classic definition: presence of 3 or more of the following criteria-body mass index greater than 2 standard deviation score, triglycerides greater than the 95th percentile, high-density lipoprotein cholesterol less than the fifth percentile, blood pressure greater than the 95th percentile, and impaired glucose tolerance. Afterward, liver steatosis was included as an additional criterion to this definition. Metabolic syndrome was diagnosed in 12 children (13.5%) according to the first definition and in 18 children (20.2%) when liver steatosis was included. The prevalence of MS increased across homeostasis model assessment of insulin resistance tertiles (P for trend = .01). The prevalence of the single components of the MS was as follows: obesity, 100%; hypertriglyceridemia, 27%; low high-density lipoprotein cholesterol, 2.2%; hypertension, 34.8%; impaired glucose tolerance, 4.5%; and nonalcoholic fatty liver disease, 21.3%. In conclusion, MS is common already among prepubertal obese children, particularly when liver steatosis is included among the diagnostic criteria. Therefore, screening for the MS should be performed in this age group; and hepatic steatosis should be considered as an additional diagnostic criterion.

Liver steatosis in obese prepubertal children: a possible role of insulin resistance.

OBJECTIVE: To determine whether in obese prepubertal children insulin resistance (IR) is associated with the development of liver steatosis. METHODS AND PROCEDURES: Cross-sectional study evaluating the prevalence of liver steatosis in 100 severely obese prepubertal children and comparing IR indexes between children with (group 1) and without steatosis (group 2). Furthermore, IR indexes were compared to values of 50 normal weight children. Fasting blood samples were collected for the evaluation of liver function tests, lipid profile, plasma glucose, and insulin levels. All children underwent an oral glucose tolerance test and anthropometric measurements. Hepatic ultrasound was performed according to international criteria and by one single operator. Analysis was performed by Mann-Whitney U-test, Pearson correlation, and logistic regression. RESULTS: Liver steatosis was found in 52% obese children and was equally distributed between the two sexes. Obese children were more insulin resistant when compared to controls (homeostasis model assessment of IR (HOMA-IR): P = 0.0001; whole body insulin sensitivity index (WBISI): P = 0.0005; fasting glucose/fasting insulin ratio (G/I): P = 0.0001), and group 1 presented an even higher degree of IR when compared to group 2 (HOMA-IR P = 0.0001; WBISI P = 0.0004; G/I P = 0.0001). The area under the curve (AUC) for insulin was significantly higher in group 1 when compared to group 2, while no difference was found in the AUC for glucose. There was no association between IR and adiposity indexes (P >0.05). The role of IR as a predictor for the development of steatosis was analyzed by multiple logistic regression, which documented that IR indexes were significantly related to steatosis independently of BMI-SDS. DISCUSSION: Liver steatosis is an emerging problem in prepubertal severely obese children, and it appears to be an association between liver steatosis and IR in these subjects.

Alterations in the oxidant-antioxidant status in prepubertal children with growth hormone deficiency: effect of growth hormone replacement therapy.

OBJECTIVE: Growth hormone deficiency (GHD) in adults is associated with increased oxidative stress determined by the underlying GH-IGF-1 axis alterations. Despite GHD being a common diagnosis in children with short stature, no data on the oxidant/antioxidant status are available in this age group. This study was designed to detect differences in oxidative stress parameters between prepubertal GH-deficient children and healthy controls. Furthermore, the effect of 12 months of conventional GH replacement (rGH) on oxidant-antioxidant status was evaluated in the GHD group only. PATIENTS: Ten (nine males and one female) prepubertal children (mean age 9.1 +/- 1.3 years) with GHD were recruited and matched for sex and age (9.2 +/- 1.9 years) with 20 healthy controls (18 males and two females). MEASUREMENTS: At study entry, lag phase, an index of susceptibility of low density lipoprotein (LDL) to in vitro oxidation, malondialdehyde (MDA) and vitamin E were measured in all subjects. These parameters were also evaluated in GH-deficient children after 12 months of rGH treatment. RESULTS: The lag phase was significantly decreased in GH-deficient children compared to healthy controls (15.50 +/- 7.4 vs. 43.00 +/- 9.2 min; P = 0.0007), while MDA was significantly increased (1.33 +/- 0.38 vs. 0.46 +/- 0.10 nmol/mg; P = 0.0006). Vitamin E levels were significantly decreased (22.44 +/- 9.57 vs. 35.38 +/- 16.49 micromol/l; P = 0.001). IGF-1 and IGFBP-3 correlated directly to lag phase (r = 0.48; P = 0.01; r = 0.63, P = 0.002, respectively) and to vitamin E (r = 0.59, P = 0.003; r = 0.58, P = 0.006, respectively). By contrast, IGF-1 and IGFBP-3 correlated indirectly to MDA (r = -0.47, P = 0.01; r =-0.65, P = 0.002, respectively). After 1 year of rGH therapy, lag phase (39.32 +/- 15.24 min; P = 0.005) and vitamin E (34.9 +/- 7.7 micromol/l; P = 0.005) increased significantly, while MDA decreased significantly (0.71 +/- 0.42 nmol/mg; P = 0.005), reaching normal levels. CONCLUSIONS: These data show that children with GHD have substantially increased oxidative stress parameters compared to healthy controls and demonstrate a normalization of these parameters after 1 year of rGH therapy.

Influence of growth hormone therapy on pituitary and lumbar spine astrocytomas. A clinical observation.

We report on a male patient with an inactive pituitary and lumbar astrocytoma. He presented with panhypopituitarism at the age of 16 and received growth hormone replacement therapy for one year. During this period the pituitary mass increased substantially and showed subsequently a consistent shrinkage once treatment was stopped. The lumbar lesion stayed stable for the whole period of observation. The presumable rGH related change of the pituitary astrocytoma underlines the importance of careful follow-up of children with growth hormone deficiency secondary to treatment for brain tumors. Substitution therapy with rGH requires further and longer studies before it can be recommended with absolute reassurance in children with subtotal resection of a pituitary astrocytoma.